WO2010004231A2

WO2010004231A2 - Novel compounds, use thereof as medicaments, and method for the preparation thereof

Info

Publication number: WO2010004231A2
Application number: PCT/FR2009/051388
Authority: WO
Inventors: Raphaël Emmanuel DUVAL; Marion Grare; Maxime Mourer; Jean-Bernard Regnouf-De-Vains
Original assignee: Universite Henri Poincare Nancy 1
Priority date: 2008-07-10
Filing date: 2009-07-10
Publication date: 2010-01-14
Also published as: FR2933692A1; US8703825B2; NZ591021A; FR2933692B1; US20110184070A1; EP2303837A2; CA2730304A1; WO2010004231A3

Abstract

The invention relates to novel compounds having the following formula (I) in which: n is an integer from 1 to 12, in particular from 1 to 8, m and m' are, independently of one another, integers from 0 to 8, - q and q' are, independently of one another, integers from 0 to 2, p and p' are, independently of one another, integers from 0 to 4, A and A' are, independently of one another, a CH₂ group, (in the particular case of amidines) an NH group or an NR" group, in which R" is a linear or branched alkyl group containing from 1 to 3 carbon atoms, - B and B' are, independently of one another, an oxygen atom or a CH₂ group, and R and R' are, independently of one another, a halogen, such as chlorine, bromine, iodine or fluorine atoms, or a linear or branched alkyl group containing from 1 to 3 carbon atoms, to the use thereof as medicaments and to the method for the preparation thereof.

Description

Novel compounds, their use as medicaments, and process for their preparation

The invention relates to novel compounds, their use as medicaments and their method of preparation.

Many molecules with anti-infectious activity (antiseptics and / or antibiotics) are known and marketed, for example hexamidine and chlorhexidine.

However, the occurrence of resistance phenomena to these molecules has been noted, and therefore, in the long run, it is more than likely that these products become ineffective because they are not usable.

Currently, nosocomial infections (NSIs) are a major public health problem. The agents responsible for IN can be bacteria, viruses or fungi.

IN means any infection occurring within at least 48 hours (for bacterial infections) or within a period corresponding to the incubation period of the germ (for viral and fungal infections) after admission or at the following a hospitalization, and if she was absent on admission to the hospital. The nosocomial character of an infection of the surgical site is asserted if it occurs within 30 days after the intervention, or in the year if it involves the implantation of foreign material (prosthesis, implant), and this although the patient is no longer hospitalized.

NNs are worrying because of their significant morbidity, associated mortality, significant additional hospital costs and the emergence of bacteria resistant to several families of antibiotics (BMR: Multi-Resistant Bacteria).

The most commonly encountered NAs are urinary tract infections (30%), respiratory infections (15%), surgical site infections (14%), and skin and soft tissue infections (10%). Among the germs responsible for IN, bacteria appear on the front line. The most commonly involved are Escherichia coli (25%) (intestinal commensal flora bacterium, responsible for urinary tract infections), Staphylococcus aureus (19%) (commensal cutaneous and nasal flora bacterium, responsible for skin infections and surgical site), Pseudomonas aeruginosa (10%) (opportunistic bacterium, responsible for severe pneumonias and skin infections), Enterococcus spp (6%) (intestinal commensal flora bacterium mainly responsible for urinary tract infections).

Globally, the antibiotic resistance rate of the bacteria responsible for IN is high and the proportion of BMR observed in France is among the largest in Europe; Northern European countries (Denmark, the Netherlands, Norway, etc.) are characterized by a very low rate of multi-resistance to antibiotics. This worrying situation is linked to excessive and often inappropriate use of antibiotics: inappropriate prescriptions, inadequate doses, inadequate treatment duration, etc.

At present, 52% of Staphylococcus aureus isolated in hospital during IN are meticillin-resistant (MRSA: Meticillin-Resistant Staphylococcus aureus), this penicillin antibiotic Staphylococci reference. Added to this is the emergence of MRSA strains resistant to many other families of antibiotics: macrolides, aminoglycosides, fluoroquinolones, even glycopeptides (antibiotics of choice in the treatment of staphylococcal infections, often last resort in case of infection. strict). Other multi-resistant hospital germs are problematic:

(i) β lactam antibiotic-resistant enterobacteria (15%) (EBLSE: Enterobacteria with extended-spectrum β-Lactamase, β-lactamases being enzymes responsible for the degradation of β-Lactamines),

(ii) glycopeptide-resistant enterococci (10%) (Vancomycin-resistant enterococci: vancomycin is a member of the glycopeptide family with teicoplanin), (iii) Pseudomonas aeruginosa resistant to cephalosporins. ^3rd generation

(25%), ...

The danger is to face a therapeutic impasse: - either no compound is no longer available for the treatment of nosocomial infections, which are generally serious since they affect weakened patients,

- Or the remaining compounds have a toxicity such that their use is limited or even not possible.

Therefore, it is essential to propose new alternative molecules with anti-infectious activity.

One aspect of the invention is to provide novel compounds for combating bacterial, viral, fungal and parasitic infections.

One aspect of the invention relates to the use of compounds for the preparation of a medicament for the treatment of bacterial, viral, fungal and parasitic infections.

In general, the invention relates to the use of at least one compound of formula

(I) following:

in which: n represents an integer from 1 to 12, in particular from 1 to 8, m and m 'independently of one another represent integers from 0 to 8, especially 1 to 8, - q and q 'represent, independently of each other, integers from 0 to 2, p and p' independently of one another represent integers from 0 to 4, - A and A 'independently represent one of the other a CH ₂ group, an NH group or a NR "group, in which R" is an alkyl group of 1 to 3 carbon atoms, linear or branched, - B and B 'represent independently one of the another an oxygen atom or a CH ₂ group,

R and R 'are, independently of one another, a halogen, such as chlorine, bromine, iodine or fluorine atoms, or an alkyl group of 1 to 3 carbon atoms, linear or branched, or a physiologically acceptable acid salt derived from a compound of formula (I) such as a hydrochloride, a formate, a trifluoroacetate or an oxalate (HOOCCOOH),

for the preparation of a medicament for the treatment of pathologies associated with bacterial, viral, fungal and parasitic infections.

The term "linear or branched alkyl group of 1 to 3 carbon atoms" denotes methyl, ethyl, n-propyl and isopropyl groups.

The term "physiologically acceptable acid salt" means that the compounds of the formula (I), defined above, may exist in the form of amidinium (when A and / or A 'are -CH ₂ -) or guanidinium (when A and / or A 'represents (nt) NH or NR ") by reaction of an inorganic acid or an organic acid with a compound of formula (I).

Examples of inorganic acids for obtaining physiologically acceptable salts include, but are not limited to, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, formic acid monohydrogenocarbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, perchloric acid, sulfuric acid, monohydrogenosulfuric acid, hydroiodic acid. Examples of organic acids for obtaining physiologically acceptable salts include, but are not limited to, acetic acid, lactic acid, propionic acid, butyric acid, isobutyric acid, lactic acid, palmic acid, maleic acid, glutamic acid, hydroxymaleic acid, malonic acid, benzoic acid, succinic acid, glycolic acid, suberic acid, fumaric acid, mandelic acid, phthalic acid, salicylic acid, benzenesulfonic acid, toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, hydroxynaphthoic acid.

Amino acid salts, such as arginates and their equivalents are also included as well as salts of organic acids such as glucuronic acid or galacturonic acid and their equivalents (see, for example, Berge et al, " Pharmaceutical Salts, "Journal of Pharmaceutical Science, 1977, 66, 1-19).

The terms "n represents an integer from 1 to 12" means all integers 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12. This definition applies to the formula (I) but also to the other formulas below. The terms "m and m" independently of one another represent integers from 0 to 8 "denote all integers 0, 1, 2, 3, 4, 5, 6, 7 and 8. This definition is applies to formula (I) but also to the other formulas below.

The terms "q and q" represent, independently of one another, whole numbers of

0 to 2 "denote the integers 0, 1 and 2. This definition applies to the formula (I) but also to the other formulas below.

The terms "p and p" independently of one another represent integers from 0 to 4 "denote integers 0, 1, 2, 3 and 4. This definition applies to formula (I) but also to the other formulas below.

The invention also relates to the use of at least one compound of formula (I) below:

in which: n represents an integer from 1 to 12, especially from 1 to 8, m and m 'independently of one another represent integers from 2 to 8, q and q' independently represent one on the other hand integers from 0 to 2, p and p 'independently of one another represent integers from 0 to 4, - A and A' represent, independently of one another, a CH group ₂ , an NH group or a NR "group, wherein R" is an alkyl group of 1 to 3 carbon atoms, linear or branched,

B and B 'represent, independently of one another, an oxygen atom or a CH ₂ group; - R and R' are, independently of each other, a halogen, such as chlorine, bromine, iodine or fluorine, or an alkyl group of 1 to 3 carbon atoms, linear or branched, or a physio-logically acceptable acid salt derived from a compound of formula (I) such as a hydrochloride, a formate, a trifluoroacetate or an oxalate (HOOCCOOH), for the preparation of a medicament for the treatment of pathologies associated with bacterial, viral, fungal and parasitic infections.

in which: n represents an integer from 1 to 12, in particular from 1 to 8, m and m 'are equal to 2, q and q' independently of one another represent integers from 0 to 2, p and p 'represent, independently of one another, integers from 0 to 4,

A and A 'independently of one another are CH ₂ , NH or NR ", wherein R" is straight or branched alkyl of 1 to 3 carbon atoms,

B and B 'represent, independently of one another, an oxygen atom or a CH ₂ group,

R and R 'are independently of each other a halogen, such as chlorine, bromine, iodine or fluorine, or an alkyl group of 1 to 3 carbon atoms, linear or branched, or a salt of physio-logically acceptable acid derived from a compound of formula (I) such as a hydrochloride, a formate, a trifluoroacetate or an oxalate (HOOCCOOH),

in which: n represents an integer from 1 to 12, in particular from 1 to 8, m and m 'independently of one another represent integers from 0 to 8, especially 1 to 8, q and q'; are equal to 0, p and p 'represent, independently of one another, integers from 0 to 4,

The invention also relates to the use of at least one compound of formula (I)

in which: n represents an integer from 1 to 12, in particular from 1 to 8, m and m 'represent, independently of one another, integers from 0 to 8, especially 1 to 8, q and q 'represent, independently of each other, integers from 0 to 2, p and p' are equal to 0, A and A 'independently of one another are CH ₂ , NH or NR ", wherein R" is straight or branched alkyl of 1 to 3 carbon atoms,

B and B 'represent, independently of one another, an oxygen atom or a CH ₂ group, or a physiologically acceptable acid salt derived from a compound of formula (I) such as a hydrochloride, a formate, trifluoroacetate or oxalate (HOOCCOOH),

in which: n represents an integer from 1 to 12, especially from 1 to 8, m and m 'are equal to 2, - q and q' are equal to 0, p and p 'independently represent one of other integers from 0 to 4,

R and R 'are independently of each other a halogen, such as chlorine, bromine, iodine or fluorine, or an alkyl group of 1 to 3 carbon atoms, linear or branched, or a salt of physio-logically acceptable acid derived from a compound of formula (I) such as a hydrochloride, a formate, a trifluoroacetate or an oxalate (HOOCCOOH), for the preparation of a medicament for the treatment of pathologies associated with bacterial, viral, fungal and parasitic infections.

in which: n represents an integer from 1 to 12, in particular from 1 to 8, m and m 'are equal to 2, q and q' independently of one another represent integers from 0 to 2, p and p 'are equal to 0,

in which : n represents an integer from 1 to 12, in particular from 1 to 8, m and m 'independently of one another represent integers from 0 to 8, especially 1 to 8,

q and q 'are equal to 0,

p and p 'are equal to 0,

in which: n represents an integer from 1 to 12, in particular from 1 to 8, m and m 'are equal to 2, q and q' are equal to 0, - p and p 'are equal to 0,

B and B 'represent, independently of one another, an oxygen atom or a CH ₂ group, or a physiologically acceptable acid salt derived from a compound of formula (I) such as a hydrochloride, a formate, a trifluoroacetate or an oxalate (HOOCCOOH),

The invention also relates to the use of at least one compound of formula (Ia) below:

in which: n represents an integer from 1 to 12, in particular from 1 to 8, m and m 'independently of one another represent integers from 0 to 8, especially 1 to 8, q and q'; independently of one another represent integers from 0 to 2, p and p 'independently of one another represent integers from 0 to 4,

A and A 'independently of one another represent an NH group or a group

NR ", in which R" is an alkyl group of 1 to 3 carbon atoms, linear or branched,

R and R 'are independently of each other a halogen, such as chlorine, bromine, iodine or fluorine, or an alkyl group of 1 to 3 carbon atoms, linear or branched, or a salt of physio-logically acceptable acid derived from a compound of formula (I) such as a hydrochloride, a formate, a trifluoroacetate or an oxalate (HOOCCOOH), for the preparation of a medicament for the treatment of pathologies associated with bacterial infections, viral, fungal and parasitic.

The compounds of formula (Ia) correspond to the compounds of formula (I) in which A and A 'represent, independently of one another, an NH group or an NR "group. According to an advantageous embodiment of the invention, the formula of the compounds for the use as defined above is the following formula (II):

in which :

B, B ', R, R', m, m ', n, p, p' are as defined above, and, - A and A 'represent, independently of one another, a CH ₂ group, an NH group or a NR "group, in which R" is a linear or branched alkyl group of 1 to 3 carbon atoms, or a physiologically acceptable acid salt derived from a compound of formula (II) such as hydrochloride, formate, trifluoroacetate or oxalate (HOOCCOOH).

The formula of the compounds of formula (II) corresponds to formula (I), in which q and q 'are equal to 0.

According to a particular embodiment of the invention, the formula of the compounds for the use as defined above is the following formula (IF):

in which :

B, B ', R, R', m, m ', n, p, p' are as defined above, and,

A and A 'independently of one another are NH or NR ", wherein R" is linear or branched alkyl of 1 to 3 carbon atoms, or a physiologically acid salt; acceptable derivative of a compound of formula (IF) such as hydrochloride, formate, trifluoroacetate or oxalate (HOOCCOOH). The formula of the compounds of formula (IF) corresponds to formula (Ia), in which q and q 'are equal to 0.

According to an advantageous embodiment of the invention, the formula of the compounds for the use as defined above is the following formula (III):

in which :

B, R, m, n, p are as defined above, and, - A represents a CH ₂ group, an NH group or a NR "group, in which R" is an alkyl group of 1 to 3 carbon atoms. carbon, linear or branched, or a physio-logically acceptable acid salt derived from a compound of formula (III) such as a hydrochloride, a formate, a trifluoroacetate or an oxalate (HOOCCOOH).

The formula of the compounds of formula (III) corresponds to formula (II), in which: m and m 'on the one hand, and p and p' on the other hand, are equal, and, - A and A 'd on the one hand, and B and B 'on the other, represent the same atom or group.

In this embodiment, the compounds of formula (III) are symmetrical.

The advantage of the molecules of formula (III) is that the preparation process is facilitated by the fact that these molecules are symmetrical.

According to an advantageous embodiment of the invention, the formula of the compounds for the use as defined above is the following formula (HF):

in which : B, R, m, n, p are as defined above, and, - A represents an NH group or a NR "group, in which R" is an alkyl group of 1 to 3 carbon atoms, linear or branched or a physiologically acceptable acid salt derived from a compound of formula (III) such as hydrochloride, formate, trifluoroacetate or oxalate (HOOCCOOH).

The formula of the compounds of formula (HF) corresponds to the formula (IF), in which: m and m 'on the one hand, and p and p' on the other hand, are equal, and

A and A 'on the one hand, and B and B' on the other hand, represent the same atom or group. In this embodiment, the compounds of formula (HF) are symmetrical.

According to an advantageous embodiment of the invention, the formula of the compound for use as defined above is the following formula (IV):

wherein n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12, or a physiologically acceptable acid salt derived from a compound of formula (IV)

The formula of the compounds of formula (IV) corresponds to formula (III), in which A represents an NH group, B an oxygen atom, p is equal to 0 and m is equal to 2. In this embodiment, the compounds of formula (IV) are symmetrical.

The advantage of the molecules of formula (IV) is that the preparation process is facilitated by the fact that these molecules are symmetrical.

According to an advantageous embodiment of the invention, the formula of the compound for use as defined above is the following formula 6:

or a physiologically acceptable acid salt derived from a compound of formula 6 such as hydrochloride, formate, trifluoroacetate or oxalate (HOOCCOOH). The formula of the compounds of formula 6 corresponds to formula (IV), wherein n is 6. In this embodiment, the compound of formula 6 is symmetrical.

According to another embodiment of the invention, the formula of the compound for the use as defined above is the formula (II) as defined above in which: m is different from m ', and / or p is different from p 'and / or R is different from R' and / or A is different from A 'and / or

- B is different from B '.

In this embodiment, compounds having such a formula are not symmetrical.

According to a particular embodiment, the compounds of the invention are involved in the treatment of pathologies caused by the bacteria of Table 1.

Table 1: Bacteria causing pathologies treated with the compounds according to the invention. According to another embodiment, the compounds of the invention are involved in the treatment of pathologies caused by multidrug-resistant bacteria (BMR) responsible for nosocomial and / or community infections.

According to another embodiment, the compounds of the invention are involved in the treatment of pathologies caused by viruses belonging to different families, such as: viral hepatitis A, B & D, C (families of Picornaviridae, Hepadnaviήdae, Flaviviridae) ; AIDS, leukemia, cancer ... (Family Retroviridae); smallpox ... (Family Poxviridae); oral and / or genital herpes, chickenpox, shingles, mononucleosis, roselose, lymphoma ... (Family Herpesviridae); SARS, colds ... (Coronaviridae family); infectious erythema (Family Parvoviridae); certain cancers ... (Families of Papovaviruses, Polyoviridae &Papillomaviridae); poliomyelitis and meningitis, viral hepatitis A (Picornaviridae family); influenza (Family Orthomyxoviridae); arboviruses (Families of Flaviviridae, Togaviridae, Rhabdoviridae, Reoviridae); Lassa fever ... (Arenaviridae family), haemorrhagic fevers (Family Bunyaviridae) ...

According to another embodiment, the compounds of the invention are involved in the treatment of pathologies caused by fungi, in particular the following fungi: Candida spp., Aspergillus spp., Epidermophyton spp., Trichophyton spp., Microsporum spp. and Pneumocystis jiroveci.

According to another embodiment, the compounds of the invention are involved in the treatment of pathologies caused by the parasites of Table 2.

Table 2: Parasites causing pathologies treated with the compounds according to the invention.

These pathologies caused by parasites may for example be parasitic diseases due to protozoa or worms, scabies, myases and pediculosis.

According to another aspect, the invention relates to the compound of formula (VI) below:

in which: n represents an integer from 1 to 12, in particular from 1 to 8, q and q 'independently of one another represent integers from 0 to 2, p and p' independently of one another represent integers from 0 to 4,

R and R 'represent, independently of one another, a halogen, such as chlorine, bromine, iodine or fluorine atoms, or an alkyl group of 1 to 3 carbon atoms, linear or branched,

R '"represents a hydrogen or a group protecting the amine function, chosen especially from the groups Boc, Fmoc, Bn, Z, if A and A' represent, independently of one another, a CH ₂ group, then m and m 'independently of one another represent integers from 1 to 8, if A and A' independently of one another represent an NH group or a group

NR ", wherein R" is an alkyl group of 1 to 3 carbon atoms, linear or branched, then m and m 'independently of one another represent integers from 2 to 8,

or a physiologically acceptable acid salt derived from a compound of formula (VI) such as a hydrochloride, a formate, a trifluoroacetate or an oxalate (HOOCCOOH),

the compounds of the following formulas being excluded:

The new compounds defined above can be used according to the present invention. The compounds of formula (VI), with the exception of the two compounds above, are new.

Examples of inorganic acids for obtaining physiologically acceptable salts include, but are not limited to, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, formic acid, monohydrogenocarbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, perchloric acid, sulfuric acid, monohydrogenosulfuric acid, hydroiodic acid.

Examples of organic acids for obtaining physiologically acceptable salts include, but are not limited to, acetic acid, lactic acid, propionic acid, butyric acid, isobutyric acid, palmic acid, maleic acid, glutamic acid, hydroxymaleic acid, malonic acid, benzoic acid, succinic acid, glycolic acid, suberic acid, fumaric acid, mandelic acid, phthalic acid, salicylic acid, benzenesulfonic acid, β-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, hydroxynaphthoic acid. Amino acid salts, such as arginates and their equivalents are also included as well as salts of organic acids such as glucuronic acid or galacturonic acid and their equivalents (see, for example, Berge et al, " Pharmaceutical Salts, "Journal of Pharmaceutical Science, 1977, 66, 1-19).

Recall that the "Boc" (or boc), "Fmoc, Bn, Z" groups respectively represent the t-butoxycarbonyl, fluorenyl-9-methoxycarbonyl, benzyl and benzyloxycarbonyl groups. According to an advantageous embodiment, the invention relates to the compound of formula (VI) defined above, in which: m and m 'independently of one another represent integers from 2 to 8.

According to an advantageous embodiment, the invention relates to the compound of formula

(VI) defined above, wherein: m and m 'are 2.

According to an advantageous embodiment, the invention relates to the compound of formula (VI) defined above, in which: q and q 'are equal to 0.

According to an advantageous embodiment, the invention relates to the compound of formula (VI) defined above, in which: p and p 'are equal to 0.

According to an advantageous embodiment, the invention relates to the compound of formula (VI) defined above, in which: m and m 'are equal to 2, and q and q' are equal to 0 to 2.

According to an advantageous embodiment, the invention relates to the compound of formula (VI) defined above, in which: m and m 'are equal to 2, and p and p' are equal to 0.

According to an advantageous embodiment, the invention relates to the compound of formula (VI) defined above, in which: q and q 'are equal to 0, and p and p' are equal to 0.

According to an advantageous embodiment, the invention relates to the compound of formula (VI) defined above, in which: m and m 'are equal to 2, q and q 'are 0, and p and p' are 0.

According to an advantageous embodiment, the invention relates to the compound of formula (VI) defined above, in which: n represents an integer from 6 to 12, in particular from 8 to 10.

According to an advantageous embodiment, the invention relates to the compound of formula (VI) defined above, in which: R, R 'represent, independently of one another, an alkyl group of 1 to 3 carbon atoms, linear or branched.

According to an advantageous embodiment, the invention relates to the compound of formula (VI) defined above, in which: n represents an integer ranging from 6 to 12, in particular from 8 to 10, and R, R 'represent independently from each other an alkyl group of 1 to 3 carbon atoms, linear or branched.

According to an advantageous embodiment, the invention relates to the compound of formula (VI) defined above, in which: n represents an integer from 6 to 12, in particular from 8 to 10, and p and p 'are equal to to 0.

The invention also relates to the compound of formula (VF) below:

in which : n represents an integer from 1 to 12, especially from 1 to 8, q and q 'independently of one another represent integers from 0 to 2, p and p' independently represent one of other integers from 0 to 4, B and B 'represent, independently of one another, an oxygen atom or a CH ₂ group,

R '"represents a hydrogen or a group protecting the amine function, chosen in particular from the groups Boc, Fmoc, Bn, Z,

A and A 'represent, independently of one another, an NH group or a NR "group, in which R" is an alkyl group of 1 to 3 carbon atoms, linear or branched, then m and m' represent independently from one another integers from 2 to 8,

the compounds of the following formulas being excluded

The new compounds defined above can be used according to the present invention. The formula of the compounds of formula (VF) corresponds to formula (VI) with A and A 'representing, independently of one another, an NH group or an NR "group.

According to an advantageous embodiment, the invention relates to compounds of formula

(I) following:

in which: n represents an integer from 1 to 12, especially from 1 to 8, q and q 'independently of one another represent integers from 0 to 2, p and p' independently represent one on the other, whole numbers from 0 to 4,

R and R 'represent, independently of one another, a halogen, such as chlorine, bromine, iodine or fluorine, or an alkyl group of 1 to 3 carbon atoms, linear or branched, if A and A' independently of one another represent a group CH ₂ , then m and m 'independently of one another represent integers from 1 to 8, if A and A' are independently of one another an NH group or a group

or a physiologically acceptable acid salt derived from a compound of formula (I) such as a hydrochloride, a formate, a trifluoroacetate or an oxalate (HOOCCOOH),

the compounds of the following formulas being excluded:

The formula of the compounds of formula (I) corresponds to formula (VI), in which R "represents a hydrogen The compounds of formula (I) above, with the exception of the two compounds above, are new.

The new compounds defined above can be used according to the present invention.

The invention also relates to compounds of formula (Ia) below

n represents an integer from 1 to 12, especially from 1 to 8, m and m 'independently of one another represent integers from 2 to 8, q and q' independently represent one of other integers from 0 to 2, p and p 'independently of one another represent integers from 0 to 4,

A and A 'independently of one another represent an NH group or a group

NR ", in which R" is an alkyl group of 1 to 3 carbon atoms, linear or branched,

B and B 'represent, independently of one another, an oxygen atom or a CH ₂ group; - R and R' are, independently of each other, a halogen, such as chlorine, bromine, iodine or fluorine, or an alkyl group of 1 to 3 carbon atoms, linear or branched, or a physio-logically acceptable acid salt derived from a compound of formula (Ia) such as a hydrochloride, a formate, a trifluoroacetate or an oxalate (HOOCCOOH), the compounds of the following formulas being excluded:

The formula of the compounds of formula (Ia) corresponds to the formula (VF), in which R "represents a hydrogen The formula of the compounds of formula (Ia) corresponds to formula (I), in which A and A 'represent independently from each other an NH group or a NR "group.

The new compounds defined above can be used according to the present invention.

The invention also relates to compounds of formula (Ib) below:

wherein: n represents an integer from 1 to 12, especially from 1 to 8, m and m 'independently of one another represent integers from 1 to 8, q and q' independently represent one on the other, integers from 0 to 2, p and p 'independently of one another represent integers from 0 to 4, B and B' represent independently of each other an atom of oxygen or a CH ₂ group, - R and R 'are independently of one another a halogen, such as chlorine, bromine, iodine or fluorine atoms, or an alkyl group of 1 to 3 carbon atoms, linear or branched, or a physiologically acceptable acid salt derived from a compound of formula (Ib) such as a hydrochloride, a formate, a trifluoroacetate or an oxalate (HOOCCOOH).

The formula of the compounds of formula (Ib) corresponds to formula (I), in which A and A 'represent a CH ₂ group. The new compounds defined above can be used according to the present invention.

According to an advantageous embodiment, the invention relates to compounds of formula (II) below:

in which :

B, B ', R, R', n, p, p 'are as defined above, and if A and A' are independently of each other a CH ₂ group, then m and m ' independently of one another represent integers from 1 to 8, if A and A 'are independently of each other an NH group or an NR "group, wherein R" is an alkyl group of 1 to 3 carbon atoms, linear or branched, then m and m 'independently of one another represent integers from 2 to 8,

or a physiologically acceptable acid salt derived from a compound of formula (II) such as hydrochloride, formate, trifluoroacetate or oxalate (HOOCCOOH).

The formula of the compounds of formula (II) corresponds to formula (I), in which q and q 'are equal to 0. The compounds of formula (II) above, excluding the two compounds above, are new.

The new compounds defined above can be used according to the present invention.

According to an advantageous embodiment, the invention relates to compounds of formula (IF) below:

in which :

B, B ', R, R', n, p, p 'are as defined above, and,

A and A 'represent, independently of one another, an NH group or a NR "group, in which R" is an alkyl group of 1 to 3 carbon atoms, linear or branched, m and m' independently represent one of the other integers from 2 to 8,

or a physiologically acceptable acid salt derived from a compound of formula (IF) such as a hydrochloride, a formate, a trifluoroacetate or an oxalate (HOOCCOOH). The formula of compounds of formula (IF) corresponds to formula (Ia), in which q and q 'are equal to 0. The formula of compounds (IF) corresponds to formula (II), in which A and A' represent independently of one another an NH group or a NR "group.

The new compounds defined above can be used according to the present invention.

According to an advantageous embodiment, the invention relates to compounds of formula (III) below:

in which :

B, R, n, p are as defined above, and, if A represents a CH ₂ group, then m represents an integer from 1 to 8, if A is an NH group or a NR "group, wherein R "is an alkyl group of 1 to 3 carbon atoms, linear or branched, then m represents an integer of 2 to 8,

or a physiologically acceptable acid salt derived from a compound of formula (III) such as hydrochloride, formate, trifluoroacetate or oxalate (HOOCCOOH).

The formula of the compounds of formula (III) corresponds to formula (II), in which: m and m 'on the one hand, and p and p' on the other hand, are equal, and A and A 'd' on the one hand, and B and B 'on the other, represent the same atom or group. In this embodiment, the compounds of formula (III) are symmetrical. The compounds of formula (III) above (excluding the two compounds above) are new.

The new compounds defined above can be used according to the present invention.

According to an advantageous embodiment, the invention relates to compounds of formula (IH ') below:

in which :

B, R, n, p are as defined above, and

A represents an NH group or a NR "group, in which R" is an alkyl group of 1 to 3 carbon atoms, linear or branched, and

m represents an integer from 2 to 8, or a physiologically acceptable acid salt derived from a compound of formula (HF) such as a hydrochloride, a formate, a trifluoroacetate or an oxalate (HOOCCOOH).

The formula of the compounds of formula (HI ') corresponds to the formula (IF), in which:

- m and m 'on the one hand, and p and p' on the other hand, are equal, and

A and A 'on the one hand, and B and B' on the other hand, represent the same atom or group. The formula of the compounds (HF) corresponds to the formula (III), in which A and A 'represent, independently of one another, an NH group or an NR "group.

The new compounds defined above can be used according to the present invention.

According to an advantageous embodiment, the invention relates to compounds of formula (IV) below:

wherein n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12, or a physiologically acceptable acid salt derived from a compound of formula (IV) such as hydrochloride, formate, trifluoroacetate or oxalate (HOOCCOOH).

The formula of the compounds of formula (IV) corresponds to formula (III), in which A represents an NH group, B an oxygen atom, p is equal to 0 and m is equal to 2. In this embodiment, the compounds of formula (IV) are symmetrical. The compounds of formula (IV) above (excluding the two compounds above) are new.

The new compounds defined above can be used according to the present invention.

According to an advantageous embodiment, the invention relates to compounds of formula 6 below:

or a physiologically acceptable acid salt derived from a compound of formula 6 such as hydrochloride, formate, trifluoroacetate or oxalate (HOOCCOOH).

The formula of the compounds of formula 6 corresponds to formula (IV), wherein n is 6. In this embodiment, the compound of formula 6 is symmetrical. The compound of formula 6 above is new.

The new compounds defined above can be used according to the present invention.

(II) as defined above, wherein: m is different from m ', and / or, p is different from p', and / or R is different from R ', and / or, - A is different of A ', and / or,

- B is different from B '. In this embodiment, compounds having such a formula are not symmetrical. The compounds of formula (II) with the characteristics defined above are new.

The new compounds defined above can be used according to the present invention.

According to another aspect, the invention relates to a pharmaceutical composition comprising as active substance at least one compound as defined above, in combination with a pharmaceutically acceptable vehicle.

In a particular embodiment, the pharmaceutical composition comprises as active substance:

a compound as defined above, for which the sum m + m '+ n is less than or equal to 10, or, - a compound as defined, for which the sum 2m + n is less than or equal to 10, said pharmaceutical composition being formulated in aqueous solution.

The first case (sum m + m '+ n) corresponds to the compounds of formulas (VI), (I) and (II). The second case (sum 2m + n) corresponds to the compounds of formulas (III), (IV) and 6, for which m is equal to m '. These compounds are soluble in aqueous solution.

In another particular embodiment, the pharmaceutical composition comprises as active substance: a compound as defined above, in particular for which the sum m + m '+ n is greater than 10, or a compound as defined above. above, for which the sum 2m + n is greater than 10, said pharmaceutical composition being formulated in hydroalcoholic solution.

The first case (sum m + m '+ n) corresponds to the compounds of formulas (VI), (I) and (II). The second case (sum 2m + n) corresponds to the compounds of formulas (III), (IV) and 6, for which m is equal to m '. When these sums are greater than 10, the compounds are rich in carbon, therefore poorly soluble in water and more lipophilic. The term "hydroalcoholic solution" denotes a mixture of water and at least one alcohol, especially chosen from ethanol, isopropyl alcohol and benzyl alcohol.

In a particular embodiment of the invention, the pharmaceutical composition as defined above is orally administrable, and in said pharmaceutical composition, the active substance is at a concentration of about 0.1 to about 5 mg / kg body weight.

In another advantageous embodiment, the pharmaceutical composition as defined above is administrable topically, and in said pharmaceutical composition, the active substance is at a concentration of about 0.1% to about 1% relative to to the total weight in the pharmaceutical composition.

The term "topically" means that the pharmaceutical composition is applied to localized locations, for example the skin or mucosa.

Various formulations are possible for said pharmaceutical compositions: in capsule, tablet, powder, cream, lotion, aqueous or hydroalcoholic solution, mouthwash, eye drops, milk, foam, gel, spray or powder, for example.

The invention also relates to the process for preparing a compound of formula (Ia) comprising the following steps of:

a) a cleavage step of the protective groups Y of a compound of formula (X ') below:

in which: n represents an integer from 1 to 12, in particular from 1 to 8, m and m 'independently of one another represent integers from 2 to 8, q and q' independently represent one of the other integers from 0 to 2, p and p 'independently of one another represent integers from 0 to 4, A and A 'independently of one another represent an NH group or a group

NR ", in which R" is an alkyl group of 1 to 3 carbon atoms, linear or branched,

Y represents a protective group of amines, in particular Boc or Fmoc.

to get :

a compound of formula (XF) below:

in which: n represents an integer from 1 to 12, especially from 1 to 8, m and m 'independently of one another represent integers from 2 to 8, q and q' independently represent one on the other integers from 0 to 2, p and p 'independently of one another represent integers from 0 to 4,

A and A 'independently of one another represent an NH group or a group

NR ", in which R" is an alkyl group of 1 to 3 carbon atoms, linear or branched,

R and R 'represent, independently of one another, a halogen, such as chlorine, bromine, iodine or fluorine atoms, or an alkyl group of 1 to 3 carbon atoms, linear or branched, or,

an acid salt derived from a compound of formula (XF) such as a hydrochloride, a formate, a trifluoroacetate or an oxalate (HOOCCOOH). b) a reaction step of the compound of formula (XF) formed in step a) with a compound of formula (XII) below:

1 (XII)

in which GP represents a Leaving Group such as -SR, -NTf or N

and Y represents a protective group of amines, in particular Boc or Fmoc,

to obtain a compound of formula (XIIF) below:

wherein: n represents an integer from 1 to 12, especially from 1 to 8, - m and m 'independently of one another represent integers from 2 to 8, q and q' independently represent number of integers from 0 to 2, p and p 'independently of one another represent integers from 0 to 4, A and A' represent, independently of one another, an NH group or a group NR ", in which R" is an alkyl group of 1 to 3 carbon atoms, linear or branched,

Y represents a protective group of amines, in particular Boc or Fmoc.

c) a deprotection step of the amino functions of the compound of formula (XIIF) obtained in step b) to obtain:

a compound of formula (Ia) below:

wherein n: n represents an integer from 1 to 12, especially from 1 to 8, m and m 'independently of one another represent integers from 2 to 8, q and q' independently represent number of integers from 0 to 2, p and p 'independently of one another represent integers from 0 to 4, - A and A' represent, independently of one another, a group NH or a group

NR ", in which R" is an alkyl group of 1 to 3 carbon atoms, linear or branched,

B and B 'represent, independently of one another, an oxygen atom or a CH ₂ group; - R and R' are, independently of each other, a halogen, such as chlorine, bromine, iodine or fluorine, or an alkyl group of 1 to 3 carbon atoms, linear or branched, or,

an acid salt derived from a compound of formula (Ia) such as a hydrochloride, a formate, a trifluoroacetate or an oxalate (HOOCCOOH).

Cleavage procedures, or deprotection, of protecting groups of protected amino functions as implemented in steps a) and c) are described in "Greene's Protective Groups in Organic Synthesis" Peter G. M. Wuts, Theodora W. Greene, Wiley. The cleavage of the boc groups can in particular be carried out in acidic medium, for example: with hydrochloric acid in aqueous solution or in organic solvent (for example dioxane or ether) (in this case, the compound is obtained as hydrochloride), or with trifluoroacetic acid, in particular in dichloromethane (in this case, the compound is obtained in the form of trifluoroacetate).

When these steps are carried out in acidic medium, the neutral form of the compound can be obtained by neutralizing the medium after reaction. However, the isolation of the compounds is facilitated when the compounds of formula (Ia), and in particular (XF), are in the form of acid salts.

Step b) makes it possible to form guanidine function. This step is generally carried out in the presence of a base, for example triethylamine or diisopropylethylamine, and as an organic solvent, such as dichloromethane, although the use of other organic solvents is also possible, for example THF, methanol, acetonitrile, dioxane, or a mixture of these solvents.

According to an advantageous embodiment, the method of preparation, as defined above, of a compound of formula (IV) comprises:

a) a cleavage step of the protective groups Y of a compound of formula (XX) below:

wherein n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12, and Y is a protecting group for amines, especially Boc or Fmoc.

to get :

a compound of formula (XXI) below:

wherein n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12, or

an acid salt derived from a compound of formula (XXI) such as a hydrochloride, a formate, a trifluoroacetate or an oxalate (HOOCCOOH),

b) a reaction step of the compound of formula (XXI) formed in step a) with a compound of formula (XII) below:

in which GP represents a Leaving Group such as -SR, -NTf or -N

and Y represents a protective group of amines, in particular Boc or Fmoc,

to obtain a compound of formula (XXII) below:

c) a deprotection step of the amino functions of the compound of formula (XXII) obtained in step b) to obtain:

a compound of formula (IV) below:

wherein n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12, or

an acid salt derived from a compound of formula (IV) such as a hydrochloride, a formate, a trifluoroacetate or an oxalate (HOOCCOOH).

The procedures for steps a), b) and c) and their characteristics are as described above for the preparation of compounds of formula (Ia).

According to another aspect, the invention relates to the compound of formula (X ') below

in which: n represents an integer from 1 to 12, especially from 1 to 8, m and m 'independently of one another represent integers from 2 to 8, q and q' independently represent one on the other integers from 0 to 2, - p and p 'independently of one another represent integers from 0 to 4,

A and A 'independently of one another represent an NH group or a group

NR ", in which R" is an alkyl group of 1 to 3 carbon atoms, linear or branched,

R and R 'independently of one another represent a halogen, such as chlorine, bromine, iodine or fluorine, or an alkyl group of 1 to 3 carbon atoms, linear or branched, Y represents a protective group amines, especially Boc or Fmoc.

in particular a compound of formula (XX) below:

The compounds of formula (X ') and (XX) are new.

According to one embodiment of the invention, the compound of formula (X ') as defined above, is an intermediate for the preparation of compounds of formula (I) such that defined above, and the compound of formula (XX) as defined above is an intermediate for the preparation of compounds of formula (IV) as defined above.

The invention also relates to the process for preparing a compound of formula (Ic), corresponding to formula (I) wherein B = O, comprising: a) a reaction step between a compound of formula (XXX) below:

(XXX) wherein ^X 1 and X 'are, independently of each other, a halogen, especially chlorine, bromine or iodine, n represents an integer from 1 to 12; , especially from 1 to 8,

with a compound of formula (XXXI) below:

in which :

m represents an integer from 1 to 8, q represents an integer from 0 to 2,

p represents an integer of 0 to 4,

R represents a halogen, such as chlorine, bromine, iodine or fluorine atoms, or an alkyl group of 1 to 3 carbon atoms, linear or branched,

b) followed by a reaction step with a compound of formula (XXXII) below:

(XXXII)

in which: - m 'represents an integer from 1 to 8, q' represents an integer from 0 to 2, p 'represents an integer from 0 to 4,

R 'represents a halogen, such as chlorine, bromine, iodine or fluorine atoms, or an alkyl group of 1 to 3 carbon atoms, linear or branched, steps a) and b) can be performed simultaneously ("one pot" reaction) or successively,

to obtain the compound of formula (XXXIII) below

(XXXIII)

in which: n represents an integer from 1 to 12, especially from 1 to 8, m and m 'independently of one another represent integers from 1 to 8, q and q' independently represent one of the other of integers from 0 to 2, p and p 'independently of one another represent integers from 0 to 4, R and R' are independently of each other a halogen, such as chlorine, bromine, iodine or fluorine atoms, or an alkyl group of 1 to 3 carbon atoms, linear or branched,

c) followed by a Pinner reaction step,

to form a compound of formula (Ic) below

in which: n represents an integer from 1 to 12, in particular from 1 to 8, m and m 'independently of one another represent integers from 1 to 8, and q' and q 'independently represent one of the other of integers from 0 to 2, p and p 'independently of one another represent integers from 0 to 4, R and R' are independently of each other a halogen, such as chlorine, bromine, iodine or fluorine atoms, or an alkyl group of 1 to 3 carbon atoms, linear or branched, or a physiologically acceptable acid salt derived from a compound of formula (Ic) such as a hydrochloride, a formate, a trifluoroacetate or an oxalate (HOOCCOOH).

Steps a) and b) in particular take place in basic medium.

The Pinner reaction comprises two steps: a reaction of the nitrile function with ethanol in the presence of acid, in particular hydrochloric acid, followed by a reaction with ammonia, to result in the formation of the amidine function .

The invention also relates to the process for the preparation of a compound of formula (Id) corresponding to formula (I) in which B = CH ₂ , comprising:

a) an alkylation step of a compound of the following formula (XXXIV)

(XXXIV)

R and R 'are, independently of one another, a halogen, such as chlorine, bromine, iodine or fluorine atoms, or an alkyl group of 1 to 3 carbon atoms, linear or branched,

to obtain a compound of formula (XXXV) below:

in which : n represents an integer from 1 to 12, especially from 1 to 8, q and q 'independently of one another represent integers from 0 to 2, p and p' independently represent one of other integers from 0 to 4, R and R 'are, independently of one another, a halogen, such as chlorine, bromine, iodine or fluorine, or an alkyl group of 1 to 3 carbon atoms, linear or branched,

X represents a leaving group, in particular a halogen atom such as the chlorine, bromine or iodine atoms

b) followed by one or more homologation steps to obtain the compound of formula

(XXXVI)

wherein: n represents an integer from 1 to 12, especially from 1 to 8, m and m 'independently of one another represent integers from 1 to 8, q and q' independently represent one on the other integers from 0 to 2, p and p 'independently of one another represent integers from 0 to 4,

c) followed by a Pinner reaction step,

to form a compound of formula (Id) below:

in which: n represents an integer from 1 to 12, in particular from 1 to 8, m and m 'independently of one another represent integers from 1 to 8, and q' and q 'independently represent one of the other of integers from 0 to 2, p and p 'independently of one another represent integers from 0 to 4, R and R' are independently of each other a halogen, such as chlorine, bromine, iodine or fluorine atoms, or an alkyl group of 1 to 3 carbon atoms, linear or branched,

or a physiologically acceptable acid salt derived from a compound of formula (Id) such as hydrochloride, formate, trifluoroacetate or oxalate (HOOCCOOH).

EXAMPLES

A. Synthesis of the compounds used as active substances

Example 1 Synthesis of 1,6-bis (4- (2-Boc-aminoethyl) phenoxy) hexane

aXSynthesis _. Already N- (t-butoxycarbpnylJ _2-

The tyramine hydrochloride (1.0 g, 5.76 mmol, 1 eq.) Is dissolved in a distilled dioxane / H2O2 mixture (25/12 mL), then a solution of NaOH (0.46 g, 11.5 g). mmol) in 10 mL of distilled water is added. The whole is stirred 10 min before the addition of di-tert-butyl-dicarbonate (BoC ₂ O) (1.26 g, 5.76 mmol, 2 eq.). The reaction is stirred overnight under argon and at room temperature. After evaporation of the dioxane, the residual aqueous phase is added with 40 ml of AcOEt, and the pH of the mixture is lowered to 7-8 using an aqueous solution of 1M HCl. The phases are then separated and the aqueous phase is washed with AcOEt (2 * 15 mL). The combined organic phases are then dried over Na ₂ SO ₄ , filtered and evaporated. The crude is then purified by chromatographic column (Al ₂ O ₃ , CH ₂ Cl ₂ / Hex, 85:15) to give N- (t-butoxycarbonyl) -2- (4-hydroxyphenyl) ethylamine (0.98 g 73%).

F ^0: 61-62 ° C.

IR (KBr): 3378.9 (-OH; -CONH-) 1686.6 (CO). UV-Vis (CH ₂ Cl ₂ ): 277 (1803).

¹ H-NMR (400 MHz, CDCl ₃ ): 1.441 (s, 9H, tert); 2.703 (t, J = 7.9 Hz, 2H, CH ₂ CH ₂ N); 3.329 (m, 2H, CH ₂ CH ₂ N); 4.602 (broad s, 1 Η, NH or OH); 6.023 (broad s, 1H, NH or OH); 6.774 (d, J = 8.3 Hz, 2H, ArH); 7.013 (d, J = 8.3 Hz, 2H, ArH). C-NMR (100 MHz, CDCl ₃ ): 28.84 (MWe ₃ ); 35.64 (CH ₂ CH ₂ N); 42.49 (CH ₂ CH ₂ N); 80.15 (CMe ₃ ); 115.97 (C _1n ); 130.18 (C ₀ ); 130.50 (Cp); 155.38 (C _φso ); 156.84 (CO). Elemental analysis calculated for C ₁₃ H ₁₉ O ₃ N (237.29): C: 65.80%; H: 8.07%; N: 5.90%; found: C: 65.77%; H: 8.09%; N: 5.90%. IE MS: 181 [M - (Me) ₃ CO - H + Na] ⁺ ; 107 [M - (Me) ₃ COC (O) NHCH ₂ ]

b) _. Synthesis _. L6: MSC4 _Λ _(Λ 2 _Boc aminoethyl 1) _ph. eno _. xχ)! iexane

N- (t-butoxycarbonyl) -2- (4-hydroxyphenyl) ethylamine (1.5 g, 6.32 mmol, leq) is dissolved in CH ₃ CN (freshly distilled over CaH ₂ ) and added with K ₂ CO ₃ (1.74 g, 12.64 mmol, 2 eq). The mixture is refluxed under argon for about two hours before the addition of dichlorohexane (0.55 mL, 3.79 mmol, 0.6 eq.). After 24 hours at reflux, 0.3 equivalents of dichloro-hexane are added. After 48 hours of reaction, the return to ambient temperature is followed by evaporation of the solvent. The crude obtained is solubilized in CH ₂ Cl ₂ and filtered on sintered glass to remove the mineral impurities. The filtrate is then concentrated to a minimum of solvent and precipitated by addition of MeOH accompanied by cold evaporation. The solid obtained is then filtered, rinsed with MeOH and dried under vacuum. It corresponds to the expected compound in the form of a white powder (0.52 g;

A variant using DMF or another amide (dimethylacetamide, N-methylpyrrolidone for example) as solvent is applicable at room temperature.

F ⁰ : 135-136 ° C.

IR (KBr): 3367.7 (CONH); 1683.4 (HNCO); 1511.3 (NH). UV-Vis (CH ₂ Cl ₂ ): 230 (22884.6); 278 (5802.7).

¹ H NMR (400 MHz, CDCl ₃ ): 1.43 (s, 18H, tert); 1.54 (m, 4H, OCH ₂ CH ₂ CH ₂ ); 1.81 (t, J = 6.0 Hz, 4H, OCH ₂ CH ₂ CH ₂ ); 2.73 (t, J = 6.6 Hz, 4H, CH ₂ CH ₂ N); 3.34 (m, 4H, CH ₂ CH ₂ N); 3.95 (t, J = 6.5 Hz, 4H, OCH ₂ CH ₂ CH ₂ ); 4.51 (bs, 2H, NH); 6.84 (d, J = 8.6 Hz, 4H, ArH); 7.09 (d, J = 8.6 Hz, 4H, ArH). NMR January ¹ 3X _/ (100 MHz, CDCl _3): 26.27 (OCH ₂ CH ₂ CH _2); 28.80 (CMe ₃ ); 29.65 (OCH ₂ CH ₂ CH ₂ ); 35.71 (CH ₂ CH ₂ N); 38.57 (CH ₂ CH ₂ N); 68.31 (OCH ₂ CH ₂ CH ₂ ); 76.62 (CMe ₃ ); 115.07 (C ₀ or C _m ); 130.06 (C ₀ or C _m ); 131.28 (C _p ); 156.26 (C _φso ); 158.18 (C _gua ). Elemental analysis calculated for C ₃₂ H ₄₈ O ₆ N ₂ (556.73): C, 69.03%; H: 8.68%; N: 5.03%; found: C, 68.98%; H: 8.57%; N: 5.07%. MS (ES ⁺ ): 557.31 [M + H ⁺ ] ⁺ .

Example 2: Synthesis of l, 6-bis (4- (2-guanidinoethyl) phenoxy) hexane 6. _aXSynthèse. dui _Λ 6: bisX4 _r χ2-aminoethyl) _[. p _. hénoxy) hexane

The 1,6-bis (4- (2-boc-aminoethyl) phenoxy) hexane (0.5 g, 0.98 mmol) is dissolved in anhydrous CH ₂ Cl ₂ (40 mL) and is added with TFA. (5 mL). The reaction remains stirring and under an inert atmosphere for about 3:30. The mixture is then concentrated to give a translucent oil, which is several times taken up in dichloromethane and concentrated to remove the maximum of residual TFA. The product obtained is then triturated in Et ₂ O to give a white solid which is then filtered, washed with Et ₂ O and dried under vacuum. It is the desired compound in the form of bis (trifluoroacetate) in the form of a white powder (0.5 g, 88%).

⁰ F: 162-163 ° C.

IR (KBr): 2956.5 (NH ₃ ⁺ ); 1676.7 (NH ₃ ⁺ ).

UV-Vis (H ₂ O): 195 (9326.7); 221 (2238.7).

¹ H-NMR (400 MHz, DMSO-D ₆ ): 1.46 (m, 4H, OCH ₂ CH ₂ CH ₂ ); 1.72 (m, 4H,

OCH ₂ CH ₂ CH ₂ ); 2.77 (t, J = 8.4 Hz, 4H, CH ₂ CH ₂ N); 2.98 (m, 4H, CH ₂ CH ₂ N); 3.94 (t, J = 6.3 Hz, 4H, OCH ₂ CH ₂ CH ₂ ); 6.88 (d, J = 8.5 Hz, 4H, ArH); 7.15 (d, J = 8.5 Hz, 4H, ArH);

7.78 (broad s, 4 Η, NH ₂ ).

¹³ C NMR (100 MHz, DMSO-D ₆ ): 25.68 (OCH ₂ CH ₂ CH ₂ ); 29.04 (OCH ₂ CH ₂ CH ₂ ); 32.56

(CH ₂ CH ₂ N); 40.59 (CH ₂ CH ₂ N); 67.79 (OCH ₂ CH ₂ CH ₂ ); 115.00 (C ₀ or C _m ); 129.34 (C _p );

130.01 (C ₀ or C _1n ); 157.95 (C _φso ). Elemental analysis calculated for C ₂₆ H ₃₄ O ₆ N ₂ F ₆ 0.5H ₂ O (593.44): C, 52.62%; H, 5.94%; N: 4.72%; found: C, 52.88%; H: 6.06%; N: 4.94%. MS (ES ⁺ ): 357.34 [M - 2 CF ₃ COOH + H ⁺ ] ⁺ . MS (ES ^"): 696.98 [M + CF ₃ COOH - H ^{^+]."}

The bis (trifluoroacetate) of 1,6-bis (4- (2-aminoethyl) phenoxy) hexane (0.3 g, 0.51 mmol;

1 eq.) Is suspended in 20 mL of anhydrous CH ₂ Cl ₂ and solubilized by the addition of a minimum of MeOH. Triethylamine Et ₃ N (0.43 mL; 3.07 mmol;. 6 eq) was then added and the Λ /, Λf'-Bis (ter ^ butoxycarbonyl) -N "-triflylguanidine (0.4 g 1.02 mmol, 2 eq) and the whole is placed at room temperature, under an inert atmosphere and with stirring for 3 h The solvent is then removed by evaporation in vacuo The crude obtained is solubilized with 30 ml of

CH ₂ Cl ₂ , washed with an aqueous solution of 2M NaHSO ₄ , then with a saturated aqueous solution of NaHCO ₃ . The organic phase is then dried over Na ₂ SO ₄ , filtered, concentrated and dried in vacuo to give the expected compound as a white powder (0.43 g, 100%).

F ⁰ : 105-106 ^° C.

IR (KBr): 3341.7 (CONH); 1725.6 (NHCO); 1572.0 (NH).

¹ H NMR (400 MHz, CDCl ₃ ): 1.47 (s, 18H, tert); 1.50 (s, 18H, tert); 1.52 (m, 4H, OCH ₂ CH ₂ CH ₂ ); 1.80 (t, J = 6.5 Hz, 4H, OCH ₂ CH ₂ CH ₂ ); 2.80 (t, J = 7.3 Hz, CH ₂ CH ₂ N);

3.62 (q, J = 7.3 Hz, 4H, CH ₂ CH ₂ N); 3.94 (t, J = 6.4 Hz, 4H, OCH ₂ CH ₂ CH ₂ ); 6.82 (d, J =

8.5 Hz, 4H, ArH); 7.11 (d, J = 8.5 Hz, 4H, ArH); 8.35 (m, 2Η, CH ₂ CH ₂ NH); 11.46 (broad s, 2H, NH).

¹³ C-NMR (100 MHz, CDCl ₃ ): 26.29 (OCH ₂ CH ₂ CH ₂ ); 22.44 (CMe ₃ ); 28.71 (CMe ₃ ); 29.66 (OCH ₂ CH ₂ CH ₂ ); 34.82 (CH ₂ CH ₂ N); 42.85 (CH ₂ CH ₂ N); 68.30 (OCH ₂ CH ₂ CH ₂ ); 79.53

(CMe ₃ ); 83.33 (CMe ₃ ); 115.07 (C ₀ or C _m ); 130.08 (C ₀ or C _m ); 130.89 (C _p ); 153.57,

156.51, 158.23, 164.03 (CO, C _φso and C _gua ). Elemental analysis calculated for C ₄₄ H ₆₈ _{O 12} N ₆ (841.05): C, 62.83%; H: 8.14%; N 9.99%; found: C, 61.26%; H: 7.84%; N: 9.99%. MS (ES ⁺ ): 841.11 [M + H ⁺ ] ⁺ .

ç) _. Synthesis of the _. L6-bi _. s _. (4 _{_-..} (2 _{_{_-...}} ^ Year idinoétiiyl) _ph_énoxy) £ hexane.

The compound 1,6-bis (4- (2- (N, N'-di-Boc) guanidinoethyl) phenoxy) hexane (0.45 g, 0.53 mmol) is dissolved in anhydrous CH ₂ Cl _2. (30 mL) and TFA (3 mL) is added. The reaction is stirred and under an inert atmosphere for about 3 hours. The mixture is then concentrated to give a translucent oil, which is several times taken up in dichloromethane and concentrated to remove the maximum of residual TFA. The product obtained is then triturated in Et ₂ O to give a white solid which is then filtered, washed with Et ₂ O and dried under vacuum. It is the desired bis (trifluoroacetate) compound of 1,6-bis (4- (2-guanidinoethyl) phenoxy) hexane in the form of a white powder (0.28 g, 79%). F ⁰ : 99-100 ^° C.

IR (KBr): 2941.0 (NH ₃ ⁺ ); 1669.7 (NH ₃ ⁺ ).

UV-Vis (H ₂ O): 196 (81810.5); 223 (19784.3).

¹ H NMR (400 MHz, D ₂ O): 1.5 (m, 4H, OCH ₂ CH ₂ CH ₂ ); 1.78 (m, 4H, OCH ₂ CH ₂ CH ₂ );

2.80 (t, J = 6.8 Hz, CH ₂ CH ₂ N); 3.42 (t, J = 6.7 Hz, 4H, CH ₂ CH ₂ N); 3.94 (t, J = 6.4 Hz, 4H, OCH ₂ CH ₂ CH ₂ ); 6.97 (d, J = 8.3 Hz, 4H, ArH); 7.23 (d, J = 8.3 Hz, 4H, ArH).

¹ H NMR (400 MHz, DMSO-D ₆ ): 1.47 (m, 4H, OCH ₂ CH ₂ CH ₂ ); 1.70 (m, 4 Η, OCH ₂ CH ₂ CH ₂ ); 2.70 (t, J = 7.3 Hz, CH ₂ CH ₂ N); 3.32 (m, 4H, CH ₂ CH ₂ N); 3.9 (t, J = 6.4 Hz, 4H, OCH ₂ CH ₂ CH ₂ ); 6.86 (d, J = 8.5 Hz, 4H, ArH); 7.16 (d, J = 8.5 Hz, 4H, ArH). ¹³ C NMR (100 MHz, DMSO-D ₆ ): 25.70 (OCH ₂ CH ₂ CH ₂ ); 27.93 (OCH ₂ CH ₂ CH ₂ ); 33.94 (CH ₂ CH ₂ N); 42.64 (CH ₂ CH ₂ N); 67.76 (OCH ₂ CH ₂ CH ₂ ); 114.77 (C ₀ or C _m ); 130.09 (C ₀ or C _1n ); 130.39 (C _p ); 157.24, 157.74 (C _ipso and C _gua ).

Elemental analysis calculated for C ₂₈ H ₃₈ O ₆ N ₆ F ₆ 0.5 H ₂ O (677.63): C, 49.63%; H: 5.80%; N: 12.40%; found: C, 50.09%; H: 5.50%; N: 11.81%. MS (ES ⁺ ): 555.17 [M - CF ₃ COOH + H ⁺ ] ⁺ ; 442.31 [M - 2 CF ₃ COOH + 2H ⁺ ] ⁺ . MS (ES ^- ): 780.93 [M + CF ₃ COOH - 2H ⁺ ] ^- ; 667.07 [M-H ⁺ ] ^- . Example 3 Synthesis of 1,6-bis (4- (2-guanidinoethyl) phenoxy) alkanes

The following compounds:

1,1-bis (4- (2-guanidinoethyl) phenoxy) methane, 1,3-bis (4- (2-guanidinoethyl) phenoxy) propane,

"1,4-bis (4- (2-guanidinoethyl) phenoxy) butane,

"1,5-bis (4- (2-guanidinoethyl) phenoxy) pentane,

"1,7-bis (4- (2-guanidinoethyl) phenoxy) heptane,

1, 8-bis (4- (2-guanidinoethyl) phenoxy) octane, 1,9-bis (4- (2-guanidinoethyl) phenoxy) nonane

1,10-bis (4- (2-guanidinoethyl) phenoxy) decane,

"1,12-bis (4- (2-guanidinoethyl) phenoxy) dodecane

are prepared according to the protocols described above to yield 1,6-bis (4- (2-guanidinoethyl) phenoxy) hexane (using respectively diiodomethane, dibromopropane, dibromobutane, dibromopentane, dibromoheptane, dibromooctane, dibromononane, dibromodecane and dibromdodecane in place of dichloro-hexane), or the corresponding dichloro-, dibromo-, diiodo or di-para-toluenesulfonylalkanes.

The characteristics of these compounds are described below.

1,1-bis (4- (2-guanidinoethyl) phenoxy) methane = compound 1

1 H-NMR (400 MHz, D ₂ O): 2.81 (t, J = 6.54 Hz, 4H, ArCH ₂ CH ₂ N); 3.39 (t, J = 6.54 Hz, 4H, ArCH ₂ CH ₂ N); 5.76 (s, 2 Η, ArCH ₂ O); 7.05 (d, J = 8.32 Hz, 4H, ArH); 7.21 (d, J = 8.28 Hz, 4H, ArH).

Elemental analysis calculated for C ₁₉ H ₂₆ N ₆ O ₂ , 2 CF ₃ COOH (598.5): C 46.16, H 4.72, N 14.04; found: C 45.95, H 4.46, N 13.69.

1,3-bis (4- (2-guanidinoethyl) phenoxy) propane = compound 3

1 H-NMR (400 MHz, D ₂ O): 2.12 (t, J = 6.0 Hz, 2H, CH ₂ CH ₂ CH ₂ ); 2.73 (t, J = 6.8 Hz, 4H, ArCH ₂ CH ₂ N); 3.32 (t, J = 6.8 Hz, 4H, CH ₂ CH ₂ N); 4.14 (t, J = 6.0 Hz, 4H, ArOCH ₂ CH ₂ ); 6.89 (d, J = 8.5 Hz, 4H, ArH); 7.13 (d, J = 8.5 Hz, 4H, ArH). Elemental analysis calculated for C ₂₅ H ₃₂ O ₆ N ₆ F ₆ 1/2 H ₂ O (635.55): C 47.24, H 5.23, N 13.22; found: C 47.20; H 5.57, N 13.52.

1,4-bis (4- (2-guanidinoethyl) phenoxy) butane = 1H-NMR-compound (400 MHz, D ₂ O): 1.83 (broad t, 4H, CH ₂ CH ₂ CH ₂ CH ₂ ); 2.74 (t, J = 6.55 Hz, 4H,

ArCH ₂ CH ₂ N); 3.32 (t, J = 6.8 Hz, 4H, ArCH ₂ CH ₂ N); 4.04 (t wide, 4 Η, ArOCH ₂ ); 6.87 (d,

J = 8.3 Hz, 4H, ArH); 7.14 (d, J = 8.3 Hz, 4H, ArH).

Elemental analysis calculated for C ₂₆ H ₃₄ O ₆ N ₆ F ₆ H ₂ O (658.59): C 47.42, H 5.51, N 12.76; found: C, 46.98; H, 5.74, N 13.37.

1,5-bis (4- (2-guanidinoethyl) phenoxy) pentane = compound 5

1 H-NMR (400 MHz, D ₂ O): 1.50 (quint, J = 6.55 Hz, 2H, CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ ); 1.72 (quint,

J = 7.0, 4H, CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ ); 2.73 (t, J = 6.55 Hz, 4H, ArCH ₂ CH ₂ N); 3.32 (t, J = 6.8

Hz, 4H, ArCH ₂ CH ₂ N); 3.98 (t, J = 6.55, 4 Η, ArOCH ₂ ); 6.87 (d, J = 8.3 Hz, 4H, ArH); 7.13 (d, J = 8.3 Hz, 4 Η, ArH).

Elemental analysis calculated for C ₂₇ H ₃₆ O ₆ N ₆ F ₆ H ₂ O (672.27): C 48.21, H 5.69, N 12.49; found: C, 48.57; H 5.77, N 12.23.

1,7-bis (4- (2-guanidinoethyl) phenoxy) heptane = compound 1H-NMR (400 MHz, D ₂ O): 1.42 (m, 6H, OCH ₂ CH ₂ CH ₂ ); 1.72 (m, 4 Η,

OCH ₂ CH ₂ CH ₂ ); 2.81 (t, J = 6.66 Hz, 4H, ArCH ₂ CH ₂ N); 3.39 (t, J = 6.68 Hz, 4H,

ArCH ₂ CH ₂ N); 4.02 (t, J = 6.42 Hz, 4H, ArOCH ₂ CH ₂ ); 6.94 (d, J = 8.32 Hz, 4H, ArH);

7.21 (d, J = 8.56 Hz, 4H, ArH)

Elemental Analyzes calculated for C ₂₅ H ₃₈ N ₆ O ₂ , 2 CF ₃ COOH (682.65): C: 51.02%; H: 5.91%; N: 12.31% Found: C: 50.72%; H: 5.96%; N: 12.24%.

1,8-bis (4- (2-guanidinoethyl) phenoxy) octane = compound 8

1 H-NMR (400 MHz, D ₂ O): 1.27 (m, 4H, CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ ); 1.34 (m, 4H, CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ ); 1.65, (quint, J = 7.0, 4H, CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ ); 2.73 (t, J = 6.8 Hz, 4H, ArCH ₂ CH ₂ N); 3.32 (t, J = 6.8 Hz, 4H, ArCH ₂ CH ₂ N); 3.96 (t, J = 6.3, 4 Η, ArOCH ₂ ); 6.87 (d, J = 8.6 Hz, 4H, ArH); 7.13 (d, J = 8.6 Hz, 4 Η, ArH).

Elemental analysis calculated for C ₃₀ H ₄₂ O ₆ N ₆ F ₆ 1 / 2H ₂ O (705.69): C 51.06, H 6.14, N 11.91; found: C 51.41; H 6.40, N 11.56. 9-bis (4- (2-guanidinoethyl) phenoxy) nonane = compound 9

1 H-NMR (400 MHz, DMSO-D ₆ ): 1.32 (m, 6H, OCH ₂ (CH ₂ ) VCH ₂ ); 1.40 (m, 4H, CH ₂ CH ₂ CH ₂ ); 1.69 (m, 4H, OCH ₂ CH ₂ CH ₂ ); 2.71 (t, J = 7.20 Hz, 4H, ArCH ₂ CH ₂ N); 3.32 (m, 4H, ArCH ₂ CH ₂ N); 3.92 (t, J = 6.40 Hz, 4H, OCH ₂ CH ₂ CH ₂ ); 6.86 (d, J = 8.80 Hz, 4H, ArH); 7.16 (d, J = 8.40 Hz, 4H, ArH); 7.52 (m, 2H, NH)

Elemental analysis calculated for C ₂₇ H ₄₂ N ₆ O ₂ , 2 CF ₃ COOH (710.71): C 52.39, H 6.24, N 11.82; found: C 52.07, H 5.95, N 11.62.

1,1-bis (4- (2-guanidinoethyl) phenoxy) decane = 1H-NMR compound (400 MHz, D ₂ O): 1.21 (m, 8H, CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ ); 1.32 (broad m, 4H, CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ ); 1.64, (quint, J = 7.0 Hz, 4H, CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ ); 2.72 (t, J = 6.55 Hz, 4H, ArCH ₂ CH ₂ N); 3.31 (t, J = 6.55 Hz, 4H, ArCH ₂ CH ₂ N); 3.96 (t, J = 6.54 Hz, 4H, ArOCH ₂ ); 6.87 (d, J = 8.6 Hz, 4H, ArH); 7.13 (d, J = 8.6 Hz, 4H, ArH). Elemental analysis calculated for C ₃₂ H ₄₆ O ₆ N ₆ F ₆ (724.73): C 53.03, H 6.40, N 11.60; found: C 53.29, H 6.49, N 11.66.

1,12-bis (4- (2-guanidinoethyl) phenoxy) dodecane = compound 12

1 H-NMR (400 MHz, D ₂ O): 1.26 (m, 12H, CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ ); 1.37 (broad m, 4H, CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ ); 1.67, (quint, J = 6.86 Hz, 4H, CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ ); 2.70 (t, J = 7.30 Hz, 4H, ArCH ₂ CH ₂ N); 3.29 (t, J = 6.52 Hz, 4H, ArCH ₂ CH ₂ N); 3.90 (t, J = 6.54 Hz, 4H, ArOCH ₂ ); 6.87 (d, J = 8.56 Hz, 4H, ArH); 7.15 (t, J = 5.56 Hz, 4H, ArH); 7.56 (t, J = 5.30 Hz, 4H, ArH). Elemental Analyzes calculated for C ₃₀ H ₄₈ N ₆ O ₂ , 2 CF ₃ COOH (752.78): C: 54.25%; H: 6.69%; N: 11.16% Found: C: 53.95%; H: 6.92%; N: 11.07%.

Example 4 Synthesis of bis (4- (amidinoalkyl) phenoxy) alkanes

1) bis (4- (cyanoalkyl) phenoxy) alkane

3- (4-hydroxyphenyl) -propionitrile is dissolved in CH3CN (freshly distilled over CaH ₂ ) and added with K2CO3. The mixture is refluxed under argon for about two hours before addition of the dichloroalkane. After 24 hours at reflux, 0.3 equivalents of dichloroalkane is added. After 48 hours of reaction, the return to ambient temperature is followed by evaporation of the solvent. The crude obtained is solubilized in CH ₂ Cl ₂ and filtered on sintered glass to remove the mineral impurities. The filtrate is then concentrated to a minimum of solvent and precipitated by addition of MeOH accompanied by cold evaporation. The solid obtained is then filtered, rinsed with MeOH and dried under vacuum.

Other protocol:

3- (4-Hydroxyphenyl) propionitrile [Heymans et al .; Bioorg. Med. Chem. 2008, 13,

1989-2007] (léq.) Is dissolved in 15 ml of DMF (dried over CaSO ₄ ) and added with K 2 CO 3 (2 eq.) And brought to 70 ^° C. for 30 minutes before addition of the dihaloalkane (0.5 eq.) . After one night at 70 ^° C., the return to ambient temperature is followed by the addition of the reaction mixture to a large volume of water, resulting in the formation of a white precipitate. The latter is then filtered on frit, rinsed with water and dried under vacuum. The solid obtained is solubilized in a minimum of CH ₂ Cl ₂ and again precipitated by the addition of an excess of MeOH. After filtration, washing with MeOH and drying, the pure expected compound is obtained in the form of white flakes.

Variants using DMF in the presence of NaH at 50 ^° C. or CH 3 CN in the presence of K ² CO 3 at 90 ^° C. are also applicable.

The propionitrile chains of this compound (bis (4- (cyanoalkyl) phenoxy) alkane) can be homologated by the following protocol:

a) hydrolysis in an acid medium to give the diacid, then esterification in ethanol in the presence of sulfuric acid, to give the diester of the following formula:

The bis-propionitrile previously obtained is hydrolyzed in a mixture of acetic acid / concentrated sulfuric acid / water at approximately 100 ^° C. The addition of cold water precipitates the diacid which is collected by filtration, washed with water and dried under water. empty. This diacid is then converted into ethyl diester by treatment with a mixture of concentrated sulfuric acid / ethanol at reflux, followed by precipitation by addition of water, filtration, washing with water and drying, then chromatography if necessary.

An alternative to this esterification may be the reaction of the diacid with two equivalents of KOH (or CsOH) in water, followed by lyophilization, yielding the double potassium salt (or cesium). This salt is reacted with about two equivalents of ethyl halide (or tosylate or mesylate) in anhydrous dimethylformamide. After chromatographic control of the end of the reaction, an excess of ice water is added to give a precipitate of the diester (or a gum) which is separated by filtration (or decantation). The crude bis (4- (2- (ethoxycarbonyl) ethyl) phenoxy) alkane diester is purified by chromatography.

b) reduction of the diester by LiAlH ₄ to give the diol of the following formula:

The ethyl diester previously obtained is treated in anhydrous THF (or diethyl ether) with one equivalent of lithium aluminum hydride. A chromatographic control incorporating a treatment of the sample according to the standard of this reaction is carried out before stopping the reaction. Excess hydride is destroyed by careful addition of water, or ethyl acetate. The solid residue is removed by filtration, and evaporation of the filtrate in vacuo gives the desired bis (4- (hydroxypropyl) phenoxy) alkane. The latter can be purified on a short column of silica or alumina.

c) halogenation of the diol with carbon tetrachloride in the presence of triphenylphosphine to give the dihalogen compound of the following formula:

The bis (4- (hydroxypropyl) phenoxy) alkane above is solubilized in dichloromethane, with two equivalents of triphenylphosphine. The solution is cooled to 0 ^° C., and an excess of carbon tetrachloride is added. The reaction medium is stirred at room temperature and the reaction is monitored by chromatography; when all the diol has disappeared, the solvents are evaporated and the residue is chromatographed on silica or alumina to give the desired bis (4- (chloropropyl) phenoxy) alkane.

The dibromo derivative can be obtained in a similar manner by replacing carbon tetrachloride with carbon tetrabromide.

A synthetic alternative may be the addition of an excess of thionyl chloride at 0 ^° C. to a solution of diol in anhydrous dichloromethane. The reaction is monitored by chromatography. When the alcohol is consumed, the solvent and the excess of thionyl chloride are distilled or evaporated under vacuum, to give the crude dichlorinated derivative, which can be chromatographed.

d) Nucleophilic substitution with NaCN on the dihalogen compound in a substitution-promoting solvent, to give the approved bis (4- (cyanoalkyl) phenoxy) alkane of the following formula:

The above bis (4- (chloropropyl) phenoxy) alkane is dissolved in dry dimethylsulfoxide, and sixteen equivalents of potassium cyanide (or sodium) are added all at once. The mixture is heated under an inert atmosphere at 80 ^° C. The reaction is monitored by chromatography. When all the dichlorinated derivative has been consumed, the mixture is cooled to room temperature and ice water is added to give a precipitate (or gum), isolated by filtration or decantation. After drying, the solid or gum obtained is chromatographed to give the desired bis (4- (cyanopropyl) phenoxy) alkane.

The set of ad steps is iterative. a) Synthesis Example of 1,3-bis (4- (2-cyanoethyl) phenoxy) propane

1989-2007 (1.0 g, 6.79 mmol, leq) is dissolved in 15 ml of DMF (dried over CaSO ₄ ) and added with K ₂ CO ₃ (1.87 g, 13.58 mmol, 2 eq.) And carried at 70 ^° C. for 30 minutes before addition of the dibromopropane (0.68 g, 3.39 mmol, 0.5 eq.). After one night at 70 ^° C., the return to ambient temperature is followed by the addition of the reaction mixture to a large volume of water, resulting in the formation of a white precipitate. The latter is then filtered on frit, rinsed with water and dried under vacuum. The solid obtained is solubilized in a minimum of CH ₂ Cl ₂ and again precipitated by the addition of an excess of MeOH. After filtration, washing with MeOH and drying, the pure expected compound is obtained in the form of white flakes (0.45 g, 41%).

Variants using DMF in the presence of NaH at 50 ^° C. or CH ₃ CN in the presence of K ₂ CO ₃ at 90 ^° C. are also applicable.

¹ H NMR (400 MHz, CDCl ₃ ): 2.24 (q, J = 6.1 Hz, 2H, OCH ₂ CH ₂ ); 2.57 (t, J = 7.3 Hz, 4H, CH ₂ CH ₂ CN); 2.88 (t, J = 6.3 Hz, 4H, CH ₂ CH ₂ CN); 4.14 (t, J = 6.0 Hz, 4H, OCH ₂ CH ₂ ); 6.88 (d, J = 8.6 Hz, 4H, ArH _O ); 7.14 (d, J = 8.6 Hz, 4H, ArH _n ).

¹³ C NMR (100 MHz, CDCl ₃ ): 19.67 (CH ₂ CH ₂ CN); 29.28 (OCH ₂ CH ₂ ); 30.74 (CH ₂ CH ₂ CN); 64.44 (OCH ₂ CH ₂ ); 114.84 (C ₀ ); 119.33 (CN); 129.38 (C _1n ); 130.28 (Cp); 158.03 (C _φso ). Elemental analysis calculated for C ₂ H ₂₂ O ₂ N ₂ (334.41): C, 75.42%; H: 6.63%; N: 8.38%; found: C, 75.51%; H: 6.70%; N: 8.42%. MS (ES ⁺ ): 335.17 [M + H ⁺ ] ⁺ ; 357.16 [M + Na ⁺ ] ⁺ .

b) Synthesis of analogous compounds The compounds

1,4-bis (4- (2-cyanoethyl) phenoxy) butane, 1,5-bis (4- (2-cyanoethyl) phenoxy) pentane, 1,6-bis (4- (2-cyanoethyl) phenoxy) hexane 1,17-bis (4- (2-cyanoethyl) phenoxy) heptane, 1,8-bis (4- (2-cyanoethyl) phenoxy) octane, 1, 9-bis (4- (2-cyanoethyl) phenoxy) nonane,

1,10-Bis (4- (2-cyanoethyl) phenoxy) decane are prepared following the procedures described above to give 1,1-bis (4- (2-cyanoethyl) phenoxy) methane (respectively using dibromopropane, dibromobutane, dibromopentane, dibromohexane, dibromoheptane, dibromooctane, dibromononane and dichlorodecane in place of dichloromethane), or the corresponding dichloro- or diiodo or di-para-toluenesulfonylalkanes.

The characteristics of these compounds are described below.

1,4-bis (4- (2-cyanoethyl) phenoxy) butane

¹ H NMR (400 MHz, CDCl ₃ ): 1.97 (m, 4H, OCH ₂ CH ₂ ); 2.57 (t, J = 7.3 Hz, 4H, CH ₂ CH ₂ CN); 2.89 (t, J = 7.3 Hz, 4H, CH ₂ CH ₂ CN); 4.02 (t, J = 5.0 Hz, 4H, OCH ₂ CH ₂ ); 6.87 (d, J = 8.6 Hz, 4H, ArH _O ); 7.15 (d, J = 8.6 Hz, 4H, ArH _n ). ¹³ C NMR (100 MHz, CDCl ₃ ): 19.67 (CH ₂ CH ₂ CN); 29.28 (OCH ₂ CH ₂ ); 30.74 (CH ₂ CH ₂ CN); 64.44 (OCH ₂ CH ₂ ); 114.84 (C ₀ ); 119.33 (CN); 129.38 (C _1n ); 130.28 (Cp); 158.03 (C _φso ). Elemental analysis calculated for C ₂ H ₂₂ O ₂ N ₂ (348.44): C, 75.83%; H: 6.94%; N: 8.03%; found: C, 75.37%; H: 6.88%; N: 7.86%.

1,5-bis (4- (2-cyanoethyl) phenoxy) pentane

¹ H-NMR (400 MHz, CDCl ₃ ): 1.63 (m, 2H, OCH ₂ CH ₂ CH ₂ ); 1.86 (m, 4H, OCH ₂ CH ₂ CH ₂ );

2.58 (t, J = 7.3 Hz, 4H, CH ₂ CH ₂ CN); 2.90 (t, J = 6.3 Hz, 4H, CH ₂ CH ₂ CN); 3.97 (t, J = 6.3 Hz, 2H, OCH ₂ ); 6.86 (d, J = 8.3 Hz, 4H, ArH); 7.14 (d, J = 8.6 Hz, 4H, ArH). ¹³ C NMR (100 MHz, CDCl ₃ ): 20.12 (CH ₂ CH ₂ CN); 23.15 (OCH ₂ CH ₂ CH ₂ ); 29.43 (OCH ₂ CH ₂ CH ₂ ); 31.18 (CH ₂ CH ₂ CN); 68.19 (OCH ₂ ); 115.23 (C ₀ ); 119.71 (CN); 129.73 (C _1n ); 130.45 (Cp); 158.63 (C _φso ).

Elemental analysis calculated for C ₂₃ H ₂₆ O ₂ N ₂ (362.46): C, 76.21%; H: 7.23%; N: 7.73%; found: C, 76.16%; H: 7.19%; N: 7.84%.

1,6-bis (4- (2-cyanoethyl) phenoxy) hexane

¹ H-NMR (400 MHz, CDCl ₃ ): 1.54 (q, OCH ₂ CH ₂ CH ₂ ); 1.81 (m, 4 Η, OCH ₂ CH ₂ CH ₂ ); 2.57 (t, J = 7.3 Hz, 4H, CH ₂ CH ₂ CN); 2.89 (t, J = 7.3 Hz, 4H, CH ₂ CH ₂ CN); 3.96 (t, J = 5.0 Hz, 4H, OCH ₂ ); 6.86 (d, J = 8.6 Hz, 4H, ArH _O ); 7.14 (d, J = 8.6 Hz, 4H, ArH _n ). ¹³ C NMR (100 MHz, CDCl ₃ ): 20.02 (CH ₂ CH ₂ CN); 26.29, 26.62 (OCH ₂ CH ₂ CH ₂ and OCH ₂ CH ₂ CH ₂ ); 31.16 (CH ₂ CH ₂ CN); 68.27 (OCH ₂ ); 115.23 (C ₀ ); 119.75 (CN); 129.74 (C _1n ); 130.44 (Cp); 158.68 (C _φso ).

Elemental analysis calculated for C ₂₄ H ₂₈ O ₂ N ₂ (376.22): C, 76.56%; H: 7.46%; N: 7.44%; found: C, 76.22%; H: 7.42%; N: 7.13%.

1,7-bis (4- (2-cyanoethyl) phenoxy) heptane

¹ H NMR (400 MHz, CDCl ₃ ): 1.46 (m, 6H, OCH ₂ CH ₂ CH ₂ CH ₂ ); 1.76 (m, 4H,

OCH ₂ CH ₂ CH ₂ CH ₂ ); 2.57 (t, J = 7.3 Hz, 4H, CH ₂ CH ₂ CN); 2.89 (t, J = 7.3 Hz, 4H, CH ₂ CH ₂ CN); 3.94 (t, J = 6.5 Hz, 4H, OCH ₂ CH ₂ ); 6.86 (d, J = 8.6 Hz, 4H, ArH _O ); 7.13 (d,

J = 8.6 Hz, 4 Η, ArH _n ).

¹³ C NMR (100 MHz, CDCl ₃ ): 19.73 (CH ₂ CH ₂ CN); 26.04, 29.17, 29.24 (OCH ₂ CH ₂ CH ₂ CH ₂ )

; 30.82 (CH ₂ CH ₂ CN); 67.98 (OCH ₂ ); 114.85 (C ₀ ); 119.36 (CN); 129.35 (C _1n ); 130.02 (Cp);

Elemental analysis calculated for C ₂₅ H ₃₀ O ₂ N ₂ (390.52): C, 76.89%; H: 7.74%; N: 7.17%

; found: C, 75.94%; H: 7.80%; N: 7.07%.

1,8-bis (4- (2-cyanoethyl) phenoxy) octane

¹ H-NMR (400 MHz, CDCl ₃ ): 1.40 (m, 4H, OCH ₂ CH ₂ CH ₂ CH ₂ ); 1.46 (m, 4 Η, OCH ₂ CH ₂ CH ₂ ); 1.78 (m, 4 Η, OCH ₂ CH ₂ ); 2.57 (t, J = 7.3 Hz, 4H, CH ₂ CH ₂ CN); 2.88 (t, J

= 7.3 Hz, 4H, CH ₂ CH ₂ CN); 3.94 (t, J = 5.0 Hz, 4H, OCH ₂ ); 6.56 (d, J = 8.6 Hz, 4H, ArH)

; 7.14 (d, J = 8.6 Hz, 4H, ArH).

¹³ C NMR (100 MHz, CDCl ₃ ): 19.70 (CH ₂ CH ₂ CN); 26.01 (OCH ₂ CH ₂ CH ₂ CH ₂ ), 29.26, 29.32

(OCH ₂ CH ₂ CH ₂ and OCH ₂ CH ₂ CH ₂ ); 31.78 (CH ₂ CH ₂ CN); 67.99 (OCH ₂ ); 114.83 (C ₀ ); 119.35 (CN); 129.33 (C _1n ); 129.99 (Cp); 158.32 (C _φso ).

Elemental analysis calculated for C ₂₆ H ₃₂ O ₂ N ₂ (404.54): C, 77.19%; H: 7.97%; N: 6.92%

; found: C, 76.75%; H: 7.80%; N: 7.66%.

1, 9-bis (4- (2-cyanoethyl) phenoxy) nonane ¹ H-NMR (400 MHz, CDCl ₃ ): 1.36 (m, 6H, OCH ₂ CH ₂ CH ₂ CH ₂ CH ₂ ); 1.45 (m, 4 Η, OCH ₂ CH ₂ CH ₂ ); 1.78 (q, 4 Η, OCH ₂ CH ₂ ); 2.58 (t, J = 7.3 Hz, 4H, CH ₂ CH ₂ CN); 2.89 (t, J = 7.3 Hz, 4H, CH ₂ CH ₂ CN); 3.93 (t, J = 6.5 Hz, 4H, OCH ₂ CH ₂ ); 6.85 (d, J = 8.6 Hz, 4H, ArH); 7.13 (d, J = 8.6 Hz, 4H, ArH). NMR 13 _/ C (100 MHz, CDCl _3): 20.12 (CH ₂ CH ₂ CN); 26.44, 29.66, 29.71, 29.88 (OCH ₂ CH ₂ CH ₂ CH ₂ CH ₂ ); 31.19 (CH ₂ CH ₂ CN); 68.40 (OCH ₂ ); 115.22 (C ₀ ); 119.71 (CN); 129.70 (C _1n ); 130.34 (Cp); 158.72 (C _φso ).

Elemental analysis calculated for C ₂₇ H ₃₄ O ₂ N ₂ (418.57): C, 77.48%; H: 8.19%; N: 6.69%; found: C, 77.35%; H: 8.12%; N: 6.76%.

1,10-bis (4- (2-cyanoethyl) phenoxy) decane

¹ H-NMR (400 MHz, CDCl ₃ ): 1.33 (m, 8H, OCH ₂ CH ₂ CH ₂ CH ₂ CH ₂ ); 1.45 (m, 4H,

OCH ₂ CH ₂ CH ₂ ); 1.78 (q, 4 Η, OCH ₂ CH ₂ ); 2.58 (t, J = 7.4 Hz, 4H, CH ₂ CH ₂ CN); 2.89 (t, J = 7.4 Hz, 4H, CH ₂ CH ₂ CN); 3.93 (t, J = 6.5 Hz, 4H, OCH ₂ CH ₂ ); 6.85 (d, J = 8.6 Hz, 4H,

ArH); 7.13 (d, J = 8.6 Hz, 4H, ArH).

¹³ C NMR (100 MHz, CDCl ₃ ): 19.75 (CH ₂ CH ₂ CN); 26.10, 29.32, 29.42, 29.55

(OCH ₂ CH ₂ CH ₂ CH ₂ CH ₂ ); 30.83 (CH ₂ CH ₂ CN); 68.08 (OCH ₂ ); 114.88 (C ₀ ); 119.37 (CN);

129.35 (C _1n ); 130.00 (Cp); 158.38 (C _φso ). Elemental analysis calculated for C ₂₈ H ₃₆ O ₂ N ₂ , 1/6 CH ₂ Cl ₂ (446.75): C: 75.72%; H: 8.19

% N, 6.27%; found: C, 75.66%; H: 8.17%; N: 6.21%.

2) bis (4- (amidinoalkyl) phenoxy) alkane

A solution of a bis (4- (cyanoalkyl) phenoxy) alkane derivative in a mixture of ethanol and anhydrous benzene is cooled to 0 ^° C. and is then treated by bubbling gaseous hydrochloric acid for approximately 1 hour. The acid solution is stored at 4 ° C for several days. The volatile portion of hydrochloric acid is removed by bubbling dry nitrogen, and the degassed solution is evaporated to dryness under reduced pressure. The evaporation residue containing bis (4- (ethyl) imidatoalkyl) phenoxy alkane dihydrochloride is taken up in an IM solution of ammonia in ethanol. The mixture is heated at 50-60 ^° C. under anhydrous conditions during 2-3h, then left stirring at room temperature overnight. The resulting medium is filtered and then diethyl ether is added, precipitating the desired bis (4- (amidinoalkyl) phenoxy) alkane dihydrochloride.

Another two-step protocol, isolating intermediate imidate compounds

The bis (4- (cyanoalkyl) phenoxy) alkane compound is dissolved in an EtOH / benzene mixture and is bubbled under stirring at 4 ° C HCl gas for about two hours. The mixture is then left stirring at room temperature for 48 hours before the evaporation in vacuo of the solvents. The oil obtained is then solubilized in a minimum of EtOH and the expected bis-imidate is precipitated by addition of a large excess of Et2O. The white precipitate is then filtered on frit, washed with Et ₂ O and dried under vacuum. The desired compound is obtained in the form of a white powder.

The bis-hydrochloride of bis (4 - [(imidato) alkyl) phenoxy) alkane is dissolved in

EtOH and gaseous NH ₃ was bubbled for about 1 h 30 min. The medium is then refluxed under argon for 5 to 6 hours. The return to ambient temperature is followed by the precipitation of the bis-amidine salt by adding an excess of Et ₂ O in the medium. The precipitate is filtered, washed with ether and dried under vacuum. The expected product is obtained in the form of a white powder.

a) Synthesis examples of imidate compounds

1,3-bis (4- (3- (ethyl-propanimidoate) phenoxy) propane bis hydrochloride

HCI The 1,3-bis (4- (2-cyanoethyl) phenoxy) propane compound (0.24 g, 0.72 mmol) is dissolved in an EtOH / benzene mixture (7/15 mL) and the mixture is bubbled under water. stirring at 4 ° C, HCl gas for about two hours. The mixture is then left stirring at room temperature for 48 hours before the evaporation in vacuo of the solvents. The oil obtained is then solubilized in a minimum of EtOH and the expected bis-imidate is precipitated by addition of a large excess of Et2O. The white precipitate is then filtered on frit, washed with Et ₂ O and dried under vacuum. The desired compound is obtained in the form of a white powder (0.24 g, 67%). ¹ H NMR (400 MHz, DMSO-D ₆ ): 1.31 (t, J = 6.9 Hz, 6H, OCH ₂ CH ₃ ); 2.14 (m, 4H, OCH ₂ CH ₂ ); 2.88 (broad s, 8 Η, ArCH ₂ CH ₂ ); 4.09 (t, J = 6.1 Hz, 4H, OCH ₂ ); 4.36 (q, J = 6.8 Hz, 4H, OCH ₂ CH ₃ ); 6.90 (d, J = 8.6 Hz, 4H, ArH); 7.16 (d, J = 8.6 Hz, 4H, ArH); 11.06, 11.79 (bs, 4H ₅ NH ₂ Cl).

Elemental analysis calculated for C ₂₅ H ₃₆ O ₄ N ₂ Cl ₂ 0.75 H ₂ O (512.98): C, 58.53%; H: 7.36%; N: 5.46%; found: C, 58.62%; H: 7.26%; N: 5.54%.

* Analogous compounds

The following compounds: 1,4-bis (4- (3- (ethyl-propanimidoate) phenoxy) butane, bis-hydrochloride-1,5-bis (4- (3- (ethyl-propanimidoate) phenoxy) pentane, bis-hydrochloride 6-bis (4- (3- (ethyl-propanimidoate) phenoxy) hexane, bis-hydrochloride 1,7-bis (4- (3- (ethyl-propanimidoate) phenoxy) heptane, bis-hydrochloride 1,8-bis (4 - (3- (Ethyl-propanimidoate) phenoxy) octane, bis-hydrochloride 1,9-bis (4- (3- (ethyl-propanimidoate) phenoxy) nonane, bis-hydrochloride-1,10-bis (4- (3- ( ethyl-propanimidoate) phenoxy) decane, bis hydrochloride are prepared following the procedures described above to yield 1,3-bis (4- (3- (ethylpropanididoate) phenoxy) propane bis hydrochloride.

The characteristics of these compounds are described below.

1,4-bis (4- (3- (ethyl-propanimidoate) phenoxy) butane bis hydrochloride

¹ H NMR (400 MHz, DMSO-D ₆ ): 1.32 (t, J = 7.1 Hz, 6H, OCH ₂ CH ₃ ); 1.85 (broad s, 4 Η, OCH ₂ CH ₂ ); 2.88 (broad s, 8 Η, ArCH ₂ CH ₂ ); 4.00 (s wide, 4 Η, OCH ₂ ); 4.36 (q, J = 6.8 Hz, 4H, OCH ₂ CH ₃ ); 6.88 (d, J = 8.6 Hz, 4H, ArH); 7.15 (d, J = 8.6 Hz, 4H, ArH); 10.98, 11.68 (broad s, NH ₂ Cl). Elemental analysis calculated for C ₂₆ H ₃₈ O ₄ N ₂ Cl ₂ 1.5H ₂ O (540.53): C, 57.77%; H: 7.64%; N: 5.18%; found: C, 57.89%; H: 7.50%; N: 5.22%.

l, 5-bis (4- (3- (ethyl-propanimidoate) phenoxy) pentane, bis hydrochloride ¹ H-NMR (400 MHz, DMSO-D _6): 1.32 (t, J = 7.1 Hz, 6H, OCH ₂ CH ₃ ), 1.56 (m, 2H, OCH ₂ CH ₂ CH ₂ ), 1.76 (q, 4 Η, OCH ₂ CH ₂ ), 2.88 (bs, 8 Η, ArCH ₂ CH ₂ ), 3.95 (t, J = 6.3 Hz, 4H, OCH ₂ ) 4.36 (q, J = 7.1 Hz, 4H, OCH ₂ CH ₃ ) 6.87 (d, J = 8.6 Hz, 4H, ArH) 7.14 (d, J = 8.6 Hz, 4H, ArH), 10.96, 11.72 (broad s, 4 Η, NH ₂ Cl).

Elemental analysis calculated for C ₂₇ H ₄₀ O ₄ N ₂ Cl ₂ 0.5 H ₂ O (536.53): C, 60.44%; H: 7.70%; N: 5.22%; found: C, 60.40%; H: 7.67%; N: 5.41%.

1,6-bis (4- (3- (ethyl-propanimidoate) phenoxy) hexane bis hydrochloride

¹ H NMR (400 MHz, DMSO-D ₆ ): 1.32 (t, J = 7.1 Hz, 6H, OCH ₂ CH ₃ ); 1.46 (broad s, 4 Η, OCH ₂ CH ₂ CH ₂ ); 1.70 (m, 4 Η, OCH ₂ CH ₂ ); 2.87 (broad s, 8 Η, ArCH ₂ CH ₂ ); 3.93 (t, J = 6.3 Hz, 4H, OCH ₂ ); 4.36 (q, J = 7.1 Hz, 4H, OCH ₂ CH ₃ ); 6.87 (d, J = 8.6 Hz, 4H, ArH); 7.14 (d, J = 8.6 Hz, 4H, ArH); 11.04, 11.64 (broad s, 4 Η, NH ₂ Cl).

Elemental analysis calculated for C ₂₈ H ₄₂ O ₄ N ₂ Cl ₂ 0.5 H ₂ O (550.56): C, 61.09%; H: 7.87%; N: 5.08%; found: C, 60.91%; H: 7.77%; N: 5.20%.

1,7-bis (4- (3- (ethyl-propanimidoate) phenoxy) heptane bis hydrochloride

¹ H NMR (400 MHz, DMSO-D ₆ ): 1.32 (t, J = 7.0 Hz, 6H, OCH ₂ CH ₃ ); 1.40 (broad s, 6 Η, OCH ₂ CH ₂ CH ₂ CH ₂ ); 1.70 (m, 4 Η, OCH ₂ CH ₂ ); 2.88 (broad s, 8 Η, ArCH ₂ CH ₂ ); 3.93 (t, J = 6.4 Hz, 4H, OCH ₂ ); 4.36 (q, J = 7.1 Hz, 4H, OCH ₂ CH ₃ ); 6.86 (d, J = 8.6 Hz, 4H, ArH); 7.14 (d, J = 8.6 Hz, 4H, ArH); 11.14, 11.58 (broad s, 4 Η, NH ₂ Cl). Elemental analysis calculated for C ₂₉ H ₄₄ O ₄ N ₂ Cl ₂ 0.75 H ₂ O (568.99): C, 61.21%; H: 8.05%; N: 4.92%; found: C, 64.41%; H: 7.95%; N: 5.11%.

1,8-bis (4- (3- (ethyl-propanimidoate) phenoxy) octane bis hydrochloride

¹ H NMR (400 MHz, DMSO-D ₆ ): 1.32 (t, J = 7.1 Hz, 6H, OCH ₂ CH ₃ ); 1.33 (broad s, 4 Η, OCH ₂ CH ₂ CH ₂ CH ₂ ); 1.41 (broad s, 4 Η, OCH ₂ CH ₂ CH ₂ ); 1.69 (q, 4 Η, OCH ₂ CH ₂ ); 2.88 (broad s, 8 Η, ArCH ₂ CH ₂ ); 3.92 (t, J = 6.4 Hz, 4H, OCH ₂ ); 4.36 (q, J = 7.1 Hz, 4H, OCH ₂ CH ₃ ); 6.86 (d, J = 8.3 Hz, 4H, ArH); 7.14 (d, J = 8.6 Hz, 4H, ArH); 10.99, 11.73 (broad s, 4 Η, NH ₂ Cl). Elemental analysis calculated for C ₂₀ H ₄₆ O ₄ N ₂ Cl ₂ 0.5H ₂ O (578.61): C, 62.27%; H: 8.18%; N: 4.84%; found: C, 62.23%; H: 8.09%; N: 5.05%.

l, 9-bis (4- (3- (ethyl-propanimidoate) phenoxy) nonane, bis hydrochloride ¹ H-NMR (400 MHz, DMSO-D _6): 1.32 (m, 12H, OCH ₂ CH ₂ CH ₂ CH ₂ CH ₂ and OCH ₂ CH ₃ ) 1.40 (m, 4 Η, OCH ₂ CH ₂ CH ₂ ) 1.69 (q, 4 Η, OCH ₂ CH ₂ ) 2.87 (s large, 8 Η, ArCH ₂ CH ₂ 3.92 (t, J = 6.4 Hz, 4H, OCH ₂ ) 4.35 (q, J = 7.1 Hz, 4H, OCH ₂ CH ₃ ), 6.86 (d, J = 8.6 Hz, 4H, ArH) 7.14 (d, J = 8.6 Hz, 4H, ArH), 10.91, 11.48 (bs, 4 Η, NH ₂ Cl).

Elemental analysis calculated for C ₃ H ₄₈ O ₄ N ₂ Cl ₂ 0.25 H ₂ O (588.13): C, 63.30%; H: 8.31%; N: 4.76%; found: C, 63.42%; H: 8.23%; N: 4.95%.

1,10-bis (4- (3- (ethyl-propanimidoate) phenoxy) decane bis hydrochloride

¹ H-NMR (400 MHz, DMSO-D ₆ ): 1.30 (brs, 6H, OCH ₂ CH ₂ CH ₂ CH ₂ CH ₂ ); 1.32 (t, J = 7.1

Hz, 6H, OCH ₂ CH ₃ ); 1.40 (m, 4 Η, OCH ₂ CH ₂ CH ₂ ); 1.68 (q, 4 Η, OCH ₂ CH ₂ ); 2.87 (broad s, 8 Η, ArCH ₂ CH ₂ ); 3.91 (t, J = 6.4 Hz, 4H, OCH ₂ ); 4.35 (q, J = 7.1 Hz, 4H, OCH ₂ CH ₃ );

6.86 (d, J = 8.6 Hz, 4H, ArH); 7.14 (d, J = 8.6 Hz, 4H, ArH); 10.92, 11.65 (s large, 4 Η,

NH ₂ Cl).

Elemental analysis calculated for C ₃₂ H ₅₀ O ₄ N ₂ Cl ₂ 0.5 H ₂ O (606.67): C, 63.35%; H: 8.47

% N: 4.61%; found: C, 63.20%; H: 8.47%; N: 4.61%.

b) Examples of synthesis of amidine compounds

1,3-bis (4- (2- (amidino) ethyl) phenoxy) propane bis hydrochloride; composed 103

HCI

The bis-hydrochloride of L3 _. rMs (4- (3- (ethyl-pro) (0.17 g,

0.34 mmol) is dissolved in 15 ml of EtOH and the NH ₃ is bubbled for approximately 1 h 30 min. The medium is then refluxed under argon for 5 to 6 hours. The return to ambient temperature is followed by the precipitation of bis-amidine by adding an excess of Et ₂ O in the medium. The precipitate is filtered, washed with ether and dried under vacuum. The expected product is obtained in the form of a white powder (0.13 g, 88%). ¹ H NMR (400 MHz, DMSO-D ₆ ): 2.15 (t, J = 6.1 Hz, 2H, OCH ₂ CH ₂ ); 2.64 (t, J = 7.8 Hz, 4H, ArCH ₂ CH ₂ or ArCH ₂ CH ₂ ); 2.88 (t, J = 7.8 Hz, 4H, ArCH ₂ CH ₂ or ArCH ₂ CH ₂ ); 3.32 (s, 2 Η, NH); 4.10 (t, J = 6.3 Hz, 4H, OCH ₂ ); 6.90 (d, J = 8.6 Hz, 4H, ArH); 7.16 (d, J = 8.6 Hz, 4H, ArH); 8.64, 9.04 (broad s, 6 Η, NH ₃ ). ¹ H NMR (400 MHz, D ₂ O): 2.06 (t, J = 5.8 Hz, 2H, OCH ₂ CH ₂ ); 2.63 (t, J = 7.3 Hz, 4H, ArCH ₂ CH ₂ or ArCH ₂ CH ₂ ); 2.85 (t, J = 7.2 Hz, 4H, ArCH ₂ CH ₂ or ArCH ₂ CH ₂ ); 4.04 (t, J = 5.8 Hz, 4H, OCH ₂ ); 6.83 (d, J = 8.3 Hz, 4H, ArH); 7.11 (d, J = 8.1 Hz, 4H, ArH). ¹³ C NMR (100 MHz, D ₂ O): 28.66, 31.55, 34.40 (OCH ₂ CH ₂ , ArCH ₂ CH ₂ ); 65.56 (OCH ₂ ); 115.37 (C ₀ ); 130.09 (C _1n ); 131.91 (CN); 157.26 (C _φso ); 170.72 (C _amidme ). Elemental analysis calculated for C ₂ H ₃₀ O ₂ N ₄ Cl ₂ 0.5H ₂ O (450.39): C, 56.00%; H: 6.93%; N: 12.43%; found: C, 56.13%; H: 6.79%; N: 12.61%.

* Analogous compounds

The following compounds:

1,4-bis (4- (2- (amidino) ethyl) phenoxy) butane, bis-hydrochloride 1,5-bis (4- (2- (amidino) ethyl) phenoxy) pentane, bis-hydrochloride 1,6- bis (4- (2- (amidino) ethyl) phenoxy) hexane, bis-hydrochloride 1,7-bis (4- (2- (amidino) ethyl) phenoxy) heptane, bis-hydrochloride-1,8-bis (4 - (2- (amidino) ethyl) phenoxy) octane, bis-hydrochloride 1,9-bis (4- (2- (amidino) ethyl) phenoxy) nonane, bis-hydrochloride 1,10-bis (4- (2- (amidino) ethyl) phenoxy) decane, bis-hydrochloride are prepared following the procedures described above to yield 1,3-bis (4- (2- (amidino) ethyl) phenoxy) propane, bis-hydrochloride.

The characteristics of these compounds are described below.

1,4-bis (4- (2- (amidino) ethyl) phenoxy) butane, bis-hydrochloride; compound 104

¹ H NMR (400 MHz, DMSO-D ₆ ): 1.85 (bs, 4H, OCH ₂ CH ₂ ); 2.64 (t, J = 7.8 Hz, 4H, ArCH ₂ CH ₂ or ArCH ₂ CH ₂ ); 2.88 (t, J = 7.8 Hz, 4H, ArCH ₂ CH ₂ or ArCH ₂ CH ₂ ); 3.31 (s, 2 Η, NH); 4.00 (s wide, 4 Η, OCH ₂ ); 6.89 (d, J = 8.3 Hz, 4H, ArH); 7.16 (d, J = 8.5 Hz, 4H, ArH); 8.58, 9.00 (broad s, 6 Η, NH ₃ ). ¹ H NMR (400 MHz, D ₂ O): 1.76 (bs, 2H, OCH ₂ CH ₂ ); 2.62 (t, J = 7.4 Hz, 4H, ArCH ₂ CH ₂ or ArCH ₂ CH ₂ ); 2.85 (t, J = 7.3 Hz, 4H, ArCH ₂ CH ₂ or ArCH ₂ CH ₂ ); 3.95 (s wide, 4 Η, OCH ₂ ); 6.82 (d, J = 8.6 Hz, 4H, ArH); 7.11 (d, J = 8.3 Hz, 4H, ArH). ¹³ C NMR (100 MHz, D ₂ O): 25.42, 31.56, 34.41 (OCH ₂ CH ₂ , ArCH ₂ CH ₂ ); 68.51 (OCH ₂ ); 115.40 (C ₀ ); 130.10 (C _1n ); 131.86 (CN); 157.26 (C _φso ); 170.72 (C _amidme ).

Elemental analysis calculated for C ₂₂ H ₃₂ O ₂ N ₄ Cl ₂ 0.5 H ₂ O (464.43): C, 56.89%; H: 6.94%; N: 12.06%; found: C, 57.31%; H: 7.40%; N: 11.41%.

1,5-bis (4- (2- (amidino) ethyl) phenoxy) pentane bis-hydrochloride; compound ¹ H-NMR (400 MHz, DMSO-D ₆ ): 1.56 (m, 2H, OCH ₂ CH ₂ CH ₂ ); 1.76 (q, 4 Η, OCH ₂ CH ₂ );

2.63 (t, J = 7.5 Hz, 4H, ArCH ₂ CH ₂ or ArCH ₂ CH ₂ ); 2.87 (t, J = 7.5 Hz, 4H, ArCH ₂ CH ₂ or

ArCH ₂ CH ₂ ); 3.94 (t, J = 6.3 Hz, 4H, OCH ₂ ); 6.87 (d, J = 8.9 Hz, 4H, ArH); 7.14 (d, J = 7.8

Hz, 4H, ArH); 8.58, 8.94 (broad s, 6 Η, NH).

¹ H NMR (400 MHz, D ₂ O): 1.55 (q, 2H, OCH ₂ CH ₂ CH ₂ ); 1.78 (q, 4 Η, OCH ₂ CH ₂ ); 2.73 (t, J = 7.4 Hz, 4H, ArCH ₂ CH ₂ or ArCH ₂ CH ₂ ); 2.95 (t, J = 7.4 Hz, 4H, ArCH ₂ CH ₂ or

ArCH ₂ CH ₂ ); 4.03 (t, J = 6.3 Hz, 4H, OCH ₂ ); 6.94 (d, J = 8.5 Hz, 4H, ArH); 7.22 (d, J = 8.3

Hz, 4H, ArH).

¹³ C NMR (100 MHz, D ₂ O): 22.14, 28.37, 31.58, 34.42 (OCH ₂ CH ₂ , ArCH ₂ CH ₂ ); 68.86

(OCH ₂ ); 115.46 (C ₀ ); 130.11 (C _1n ); 131.86 (CN); 157.31 (C _φso ); 170.73 (C _amidme ). Elemental analysis calculated for C ₂₃ H ₃₄ O ₂ N ₄ Cl ₂ , 0.5 H ₂ O, 0.5 NH ₄ Cl (505.19): C, 54.68

% H: 7.38%; N: 12.47%; found: C, 54.36%; H: 7.26%; N: 12.66%.

1,6-bis (4- (2- (amidino) ethyl) phenoxy) hexane bis-hydrochloride; compound 106

¹ H NMR (400 MHz, DMSO-D ₆ ): 1.47 (bs, 4H, OCH ₂ CH ₂ CH ₂ ); 1.72 (broad s, 4 Η, OCH ₂ CH ₂ ); 2.64 (t, J = 7.8 Hz, 4H, ArCH ₂ CH ₂ or ArCH ₂ CH ₂ ); 2.87 (t, J = 7.8 Hz, 4H,

ArCH ₂ CH ₂ or ArCH ₂ CH ₂ ); 3.94 (t, J = 6.3 Hz, 4H, OCH ₂ ); 6.87 (d, J = 8.3 Hz, 4H, ArH);

7.15 (d, J = 8.1 Hz, 4H, ArH); 8.60, 9.02 (broad s, 6 Η, NH).

¹ H NMR (400 MHz, D ₂ O): 1.32 (brs, 4H, OCH ₂ CH ₂ CH ₂ ); 1.58 (m, 4 Η, OCH ₂ CH ₂ );

2.62 (t, J = 7.5 Hz, 4H, ArCH ₂ CH ₂ or ArCH ₂ CH ₂ ); 2.84 (t, J = 7.4 Hz, 4H, ArCH ₂ CH ₂ or ArCH ₂ CH ₂ ); 3.86 (t, J = 6.4 Hz, 4H, OCH ₂ ); 6.80 (d, J = 8.6 Hz, 4H, ArH); 7.11 (d, J =

8.3 Hz, 4H, ArH).

¹³ C NMR (100 MHz, D ₂ O): 25.42, 28.62, 31.56, 34.41 (OCH ₂ CH ₂ CH ₂ , ArCH ₂ CH ₂ ); 68.86

(OCH ₂ ); 115.38 (C ₀ ); 130.08 (C _1n ); 131.80 (CN); 157.34 (C _φso ); 170.72 (C _amidme ). Elemental analysis calculated for C ₂₄ H ₃₆ O ₂ N ₄ Cl ₂ , 1/3 NH ₄ Cl (501.3): C, 57.50%; H: 7.50%; N: 12.10%; found: C, 57.13%; H: 7.05%; N: 12.10%.

1,7-bis (4- (2- (amidino) ethyl) phenoxy) heptane, bis-hydrochloride; compound ¹ H-NMR (400 MHz, DMSO-D ₆ ): 1.41 (brs, 6H, OCH ₂ CH ₂ CH ₂ CH ₂ ); 1.71 (m, 4H, OCH ₂ CH ₂ ); 2.63 (t, J = 7.1 Hz, 4H, ArCH ₂ CH ₂ or ArCH ₂ CH ₂ ); 2.87 (t, J = 7.8 Hz, 4H, ArCH ₂ CH ₂ or ArCH ₂ CH ₂ ); 3.93 (t, J = 6.3 Hz, 4H, OCH ₂ ); 6.87 (d, J = 8.6 Hz, 4H, ArH); 7.15 (d, J = 8.3 Hz, 4H, ArH); 8.57, 9.00 (broad s, 6 Η, NH).

¹ H-NMR (400 MHz, D ₂ O): 1.16 (bs, 6H, OCH ₂ CH ₂ CH ₂ CH ₂ ); 1.49 (m, 4 Η, OCH ₂ CH ₂ ); 2.56 (t, J = 7.5 Hz, 4H, ArCH ₂ CH ₂ or ArCH ₂ CH ₂ ); 2.76 (t, J = 7.3 Hz, 4H, ArCH ₂ CH ₂ or ArCH ₂ CH ₂ ); 3.69 (t, J = 6.3 Hz, 4H, OCH ₂ ); 6.69 (d, J = 8.3 Hz, 4H, ArH); 7.04 (d, J = 8.6 Hz, 4H, ArH).

¹³ C NMR (100 MHz, D ₂ O): 25.75, 28.90, 28.94, 31.58, 34.43 (OCH ₂ CH ₂ CH ₂ CH ₂ , ArCH ₂ CH ₂ ); 68.61 (OCH ₂ ); 115.16 (C ₀ ); 129.99 (C _1n ); 131.66 (CN); 157.46 (C _ipso ); 170.66 (Caπnώne).

Elemental analysis calculated for C ₂₅ H ₃₈ O ₂ N ₄ Cl ₂ 0.5 H ₂ O (497.5): C, 59.28%; H: 7.75%; N: 11.06%; found: C, 58.74%; H: 7.46%; N: 11.47%.

1,8-bis (4- (2- (amidino) ethyl) phenoxy) octane, bis-hydrochloride; compound ¹ H-NMR (400 MHz, DMSO-D ₆ ): 1.47 (bs, 4H, OCH ₂ CH ₂ CH ₂ ); 1.72 (broad s, 4 Η, OCH ₂ CH ₂ ); 2.64 (t, J = 7.8 Hz, 4H, ArCH ₂ CH ₂ or ArCH ₂ CH ₂ ); 2.87 (t, J = 7.8 Hz, 4H, ArCH ₂ CH ₂ or ArCH ₂ CH ₂ ); 3.31 (s, 2 Η, NH); 3.94 (t, J = 6.3 Hz, 4H, OCH ₂ ); 6.87 (d, J = 8.3 Hz, 4H, ArH); 7.15 (d, J = 8.1 Hz, 4H, ArH); 8.60, 9.02 (broad s, 6 Η, NH ₃ ). ¹ H-NMR (400 MHz, D ₂ O): 1.25 (m, 4H, OCH ₂ CH ₂ CH ₂ CH ₂ ); 1.42 (m, 4 Η, OCH ₂ CH ₂ CH ₂ ); 1.63 (m, 4 Η, OCH ₂ CH ₂ ); 2.62 (t, J = 7.4 Hz, 4H, ArCH ₂ CH ₂ or ArCH ₂ CH ₂ ); 2.85 (t, J = 7.3 Hz, 4H, ArCH ₂ CH ₂ or ArCH ₂ CH ₂ ); 3.93 (t, J = 6.1 Hz, 4H, OCH ₂ ); 6.85 (d, J = 8.6 Hz, 4H, ArH); 7.12 (d, J = 8.6 Hz, 4H, ArH).

¹³ C NMR (100 MHz, D ₂ O): 25.83, 28.90, 29.19, 31.58, 34.43 (OCH ₂ CH ₂ CH ₂ CH ₂ , ArCH ₂ CH ₂ ); 68.76 (OCH ₂ ); 115.22 (C ₀ ); 130.00 (C _1n ); 131.61 (CN); 157.43 (C _φso ); 170.65 (Caπndine).

Elemental analysis calculated for C ₂₆ H ₄₀ O ₂ N ₄ Cl ₂ , 0.4 H ₂ O (518.73): C, 60.20%; H: 7.92%; N: 10.80%; found: C, 60.34%; H: 7.85%; N: 10.91%. 9-bis (4- (2- (amidino) ethyl) phenoxy) nonane, bis-hydrochloride; compound 109

¹ H-NMR (400 MHz, DMSO-D ₆ ): 1.31 (bs, 6H, OCH ₂ CH ₂ CH ₂ CH ₂ CH ₂ ); 1.40 (bs, 4H, OCH ₂ CH ₂ CH ₂ ); 1.68 (q, 4 Η, OCH ₂ CH ₂ ); 2.66 (t, J = 7.8 Hz, 4H, ArCH ₂ CH ₂ or ArCH ₂ CH ₂ ); 2.88 (t, J = 7.8 Hz, 4H, ArCH ₂ CH ₂ or ArCH ₂ CH ₂ ); 3.91 (t, J = 6.4 Hz, 4H, OCH ₂ ); 6.85 (d, J = 8.3 Hz, 4H, ArH); 7.16 (d, J = 8.6 Hz, 4H, ArH); 8.77, 9.16 (broad s, 8 Η, NH).

¹ H NMR (400 MHz, D ₂ O): 1.32 (m, 6H, OCH ₂ CH ₂ CH ₂ CH ₂ CH ₂ ); 1.41 (m, 4 Η, OCH ₂ CH ₂ CH ₂ ); 1.73 (q, 4 Η, OCH ₂ CH ₂ ); 2.73 (t, J = 7.4 Hz, 4H, ArCH ₂ CH ₂ or ArCH ₂ CH ₂ ); 2.95 (t, J = 7.4 Hz, 4H, ArCH ₂ CH ₂ or ArCH ₂ CH ₂ ); 4.04 (t, J = 6.5 Hz, 4H, OCH ₂ ); 6.96 (d, J = 8.6 Hz, 4H, ArH); 7.22 (d, J = 8.3 Hz, 4H, ArH).

¹³ C NMR (100 MHz, D ₂ O): 25.89, 29.07, 29.32, 31.47, 34.02 (OCH ₂ CH ₂ CH ₂ CH ₂ CH ₂ , ArCH ₂ CH ₂ ); 67.69 (OCH ₂ ); 114.71 (C ₀ ); 129.63 (C _1n ); 131.40 (CN); 157.67 (C _ipso ); 170.51

(, The friend dinej-

Elemental analysis calculated for C ₂₇ H ₄₂ O ₂ N ₄ Cl ₂ (525.55): C, 60.70%; H: 8.06%; N: 10.66%; found: C, 61.59%; H: 7.97%; N: 10.58%.

1,10-bis (4- (2- (amidino) ethyl) phenoxy) decane, bis-hydrochloride; compound 110

¹ H-NMR (400 MHz, DMSO-D ₆ ): 1.29 (m, 8H, OCH ₂ CH ₂ CH ₂ CH ₂ CH ₂ ); 1.39 (m, 4 Η, OCH ₂ CH ₂ CH ₂ ); 1.68 (m, 4 Η, OCH ₂ CH ₂ ); 2.65 (t, J = 7.8 Hz, 4H, ArCH ₂ CH ₂ or ArCH ₂ CH ₂ ); 2.88 (t, J = 7.8 Hz, 4H, ArCH ₂ CH ₂ or ArCH ₂ CH ₂ ); 3.36 (s, 2 Η, NH); 3.91 (t, J = 6.3 Hz, 4H, OCH ₂ ); 6.86 (d, J = 8.3 Hz, 4H, ArH); 7.16 (d, J = 8.3 Hz, 4H, ArH); 8.74, 9.12 (broad s, 6 H ₅ NH ₃ ).

¹ H-NMR (400 MHz, D ₂ O): 1.29 (m, 8H, OCH ₂ CH ₂ CH ₂ CH ₂ CH ₂ ); 1.40 (m, 4 Η, OCH ₂ CH ₂ CH ₂ ); 1.72 (q, 4 Η, OCH ₂ CH ₂ ); 2.71 (t, J = 7.3 Hz, 4H, ArCH ₂ CH ₂ or ArCH ₂ CH ₂ ); 2.94 (t, J = 7.3 Hz, 4H, ArCH ₂ CH ₂ or ArCH ₂ CH ₂ ); 4.03 (t, J = 6.5 Hz, 4H, OCH ₂ ); 6.95 (d, J = 8.6 Hz, 4H, ArH); 7.21 (d, J = 8.8 Hz, 4H, ArH). ¹³ C NMR (100 MHz, D ₂ O): 25.89, 29.07, 29.13, 29.31, 31.45, 34.99 (OCH ₂ CH ₂ CH ₂ CH ₂ , ArCH ₂ CH ₂ ); 67.69 (OCH ₂ ); 114.73 (C ₀ ); 129.62 (C _1n ); 131.37 (CN); 157.68 (C _φso );

170.42 (Caπndine). Elemental analysis calculated for C ₂₈ H ₄₄ O ₂ N ₄ Cl ₂ 0.5H ₂ O (548.59): C, 61.30%; H: 8.26%; N: 10.21%; found: C, 61.39%; H: 8.12%; N: 10.16%. Example 5 Synthesis of bis (para-cyanomethyl) -diphenylalkane

The 1,2-diphenylalkane is treated with dichloromethylether in the presence of zinc chloride (Hager et al., J. AM Pharm Ass, 1952, XLI, 3 (6), 115-118, Reichstein and Oppenauer, HeIv. Chim. Acta, 1933, 16, 1380) or with chloromethyl-n-octyl ether in the presence of titanium tetrachloride, or any other chloromethylating agent, to give bis (para-chloromethyl) -diphenylalkane.

Bis (para-chloromethyl) -diphenylalkane is treated with NaCN in a hydroalcoholic mixture (Hager et al., J. AM Pharm Ass, 1952, XLI, 3 (6), 115-118, Reichstein and Oppenauer, HeIv. Chim. Acta, 1933, 16, 1380), or in any other solvent promoting this nucleophilic substitution to give the bis (para-cyanomethyl) -diphenylalkane

These compounds can be registered using the previously proposed protocol.

Example 6 Synthesis of bis (para-guanidinoalkyl) phenoxyalkanes

1) bis (para-aminoalkyl) phenyl) alkanes

The bis (4-cyanoalkyl) -diphenylalkane in question is dissolved in anhydrous THF under an inert atmosphere. Between 5 and 10 equivalents of borane complex: 1M THF in tetrahydrofuran are added, and the mixture is stirred for 30 minutes at room temperature and then brought to reflux for 3 to 4 hours. After cooling to room temperature, the mixture is added to excess methanol to destroy the excess borane. Trimethoxyborane, methanol and tetrahydrofuran are evaporated. The evaporation residue is taken up in a methanol / water / hydrochloric acid mixture, and the mixture is refluxed for 2 hours. The solvents are evaporated to dryness to give the desired bis (4 - ((aminomethyl) alkyl) diphenylalkane dihydrochloride The free bisamine is obtained by treatment of an aqueous solution of hydrochloride in the presence of a mineral base, followed by The organic phase is dried over sodium sulphate, filtered and evaporated under reduced pressure.

2) bis (4- (N, N-di-Bo) guanidinoalkyl) phenyl) alkane

The bis (4-aminoalkyl) phenyl alkane dihydrochloride is suspended in anhydrous CH ₂ Cl ₂ and solubilized by the addition of a minimum of MeOH. Triethylamine is then added, as well as Λ /, N'-Bis (tert-butoxycarbonyl) -N "-triflylguanidine and the whole is placed at room temperature, under an inert atmosphere and with stirring.The solvent is removed by evaporation under The crude product obtained is solubilized with CH ₂ Cl ₂ , washed with an aqueous solution of 2M NaHSO ₄ , then with a saturated aqueous solution of NaHCO 3, and the organic phase is then dried over Na ₂ SO ₄ , filtered, concentrated and dried. under vacuum to give the protected compound.

3) bis (4-guanidinoalkyl) phenyl) alkane

CFXO ₉ H

NH NH

CF, COOH The bis (4- (7V, 6'-di-Boc) guanidinoalkyl) phenyl) alkane compound is dissolved in anhydrous CH ₂ Cl ₂ and is added with TFA. The reaction is stirred and under an inert atmosphere for about 3 hours. The mixture is then concentrated, repeated several times with dichloromethane and concentrated to remove the maximum of residual TFA. The product obtained is then triturated in Et ₂ O to give a solid which is then filtered, washed with Et ₂ O and dried under vacuum. It is the desired compound bis (trifluoroacetate) bis (4- (guanidinoalkyl) phenyl) alkane.

Example 7 Synthesis of bis (4- (amidinoalkyl) phenyl) alkanes

A solution of a bis (4- (cyanoalkyl) phenyl) alkane derivative in a mixture of ethanol and anhydrous benzene is cooled to 0 ^° C. and is then treated by bubbling gaseous hydrochloric acid for approximately 1 hour. The acid solution is stored at 4 ° C for several days. The volatile portion of hydrochloric acid is removed by bubbling dry nitrogen, and the degassed solution is evaporated to dryness under reduced pressure. The evaporation residue, containing bis (4- (ethyl) imidatoalkyl) phenyl) alkane dihydrochloride, is taken up in an IM solution of ammonia in ethanol. The mixture is heated at 50-60 ⁰ C under anhydrous conditions for 2-3h, then is left stirring at room temperature overnight. The resulting medium is filtered and then diethyl ether is added, causing the precipitation of the desired bis (4- (amidinoalkyl) phenyl) alkane dihydrochloride. B. Determination of biological activity

Equipment used

Spuhes _. bacterial

According to the joint recommendations:

- the "Committee of the Antibiogram of the French Society of Microbiology" (CA-SFM) [CA-SFM. Communiqué 2007 (Edition January 2007). http://www.sfm.asso.fr] and - the CLSI, formerly known as the National Committee for Clinical Laboratory Standards (NCCLS). 2003. Methodes for antimicrobial dilution susceptibility tests for bacteria that grow aerobically; approved standard M7-A6, 6th ed. National Committee for Clinical Laboratory Standards, Wayne, PA, USA.], Five reference bacterial strains were used for the study: Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853, Staphylococcus aureus ATCC 25923 & ATCC 29213 and Enterococcus faecalis ATCC 29212 .

The study also included 5 clinical isolates obtained from rectal swabs and / or blood culture:

Penicillin-producing E. coli (EcR1),

- S. aureus resistant to meticillin (A gene type) (SaRl),

- E.faecium resistant to vancomycin (vanB gene) (EfR1),

- E. faecalis resistant to teicoplanin and vancomycin (van A gene) (EfR2), and, - P. aeruginosa overexpressing an efflux pump (PaR1).

The isolates were chosen on the basis of their resistance profile. Resistance profiles were determined on VITEK2 (BioMerieux, France).

The bacteria are cultured either on Mueller-Hinton agar (Difco, 225250) or Mueller-Hinton broth (Difco, 275730), at 35 ° C (Grare M, Mourer M, Fontanay S, Regnouf- de- Vains JB, Finance C, Duval RE. In vitro activity of para-guanidinoethylcalix [4] arene against susceptible and antibiotic-resistant Gram-negative and Gram-positive bacteria. J.

Antimicrob Chemother. 2007; 60: 575-81]. Active substances

The different molecules tested were prepared in the form of aqueous solution at 10 ^-2 mol / l. The solutions used for the biological tests are freshly prepared and stored for a maximum of one week at 4 ° C. The solutions are filtered through a 0.22 μm pore filter (Millex®GP, 0.22 μm, Millipore, France) before each test.

Thirteen active substances were tested: guanidino compounds 1, 3, 4, 6, 7, 9 and 10 in the form of trifluoroacetic acid salts, amidino compounds 103, 104, 106, 107, 108 and 110 in the form of salts. hydrochloric acid, as well as chlorhexidine in the form of gluconic acid salt, and hexamidine in the form of isethionic acid salt, which are marketed antibacterials, for comparison.

CF ₃ COOH CF ₃ COOH

CF ₃ COOH CF ₃ COOH

HCl HCl

HCl HCl

HCl HCl

HCl HCl

HCl HCl

HCl HCl

Example 8: Determination of antibacterial activity

Procedure for Determining Minimal Inhibitory Concentration (MIC)

Minimum Inhibitory Concentrations (MICs) were determined by the standardized microdilution method in a liquid medium (U-bottomed 96-well microplate, Greiner), in Mueller-Hinton broth, with a final inoculum of 10 ⁵ -10 ⁶ CFU. / mL, depending on bacterial species, as recommended by CLSI.

For the determination of MICs, bacterial suspensions are prepared from an isolated colony taken from Mueller-Hinton agar taken up in 5 mL of Mueller-Hinton broth. After 24 hours of growth, the bacterial suspensions are diluted in sterile distilled water to obtain an inoculum of 10 ⁵ - 10 ⁶ CFU / mL. The purity of the bacterial suspensions is controlled by agar isolation and Gram stain.

After 18 to 24 hours of incubation at 35 ° C., the MICs are determined using an ELISA plate reader (at 540 nm, Multiskan EX, Thermo Electron Corporation, France) as the concentrations of active substance for the absorbance is comparable to that of the negative control (culture medium alone or with the drug, without the inoculum). The results are the average of 4 independent experiments.

Results

Minimum inhibitory concentrations (MIC) are given in Table 3.

'M

Table 3.1: MIC values (mg / L) obtained by the liquid microdilution method, according to the procedures of CLSI and CA-SFM.

1.: 1,1-bis (4- (2-guanidinoethyl) phenoxy) methane; 3: 1,3-bis (4- (2-guanidinoethyl) phenoxy) propane;

4: 1, 4-bis (4- (2-guanidinoethyl) phenoxy) butane; 6: 1, 6-bis (4- (2-guanidinoethyl) phenoxy) hexane;

7: 1, 7-bis (4- (2-guanidinoethyl) phenoxy) heptane; 9: 1, 9-bis (4- (2-guanidinoethyl) phenoxy) nonane;

10: 1,10-bis (4- (2-guanidinoethyl) phenoxy) decane; nd: not determined.

Table 3.2: MIC values (mg / L) obtained by the liquid microdilution method, according to the procedures of CLSI and CA-SFM.

103 1,3-bis (4- (2-amidinoethyl) phenoxy) propane; 104: 1,4-bis (4- (2-amidinoethyl) phenoxy) butane; 105 1,5-bis (4- (2-amidinoethyl) phenoxy) pentane; 106: 1,6-bis (4- (2-amidinoethyl) phenoxy) hexane; 107 1,7-bis (4- (2-amidinoethyl) phenoxy) heptane; 108: 1,8-bis (4- (2-amidinoethyl) phenoxy) octane;

109 1,9-bis (4- (2-amidinoethyl) phenoxy) nonane; 110: 1,10-bis (4- (2-amidinoethyl) phenoxy) decane. nd: not determined.

Firstly, both hexamidine and chlorhexidine have broad-spectrum antibacterial activity (ie, antibacterial activity against Gram-positive and Gram-negative bacteria), with these two molecules (hexamidine and chlorhexidine) having a lower activity on P. aeruginosa. In addition, hexamidine and chlorhexidine exhibit comparable antibacterial activity whether reference bacteria (ATCC strains) or clinical isolates are considered. Finally, hexamidine and chlorhexidine show better activity on gram-positive shells (S. aureus and Enterococcus spp., With the exception of chlorhexidine with respect to E. coli bacteria.

Secondly, concerning the compounds according to the invention, the antibacterial activity varies according to the length of the alkyl chain (guanidino: n = 9> n = 10> n = 6> n = 4> n = 3> n = 1 amidino: n = 10> n = 6> n = 4). These molecules show activity on Gram-positive and Gram-negative bacteria, with a higher activity on Gram-positive cocci (and more particularly Staphylococcus spp., And S. aureus), and 6 maintain comparable activity on isolates. clinics.

Compound 6 exhibits an overall antibacterial activity better than hexamidine and comparable to that of chlorhexidine, in particular as regards its activity with respect to Staphylococci. Compounds 9 and 10 both show very good activity on the 5 reference strains tested, equivalent or superior to those of compound 6.

Example 9 Determination of Cell Viability and Cytotoxicity

Cell lines and cell culture

The eukaryotic cells used in our study are the HaCaT cells (human keratinocytes) which were graciously provided by the Pierre Fabre Institute (Toulouse, France); and MRC-5 cells (human embryonic fibroblasts) which were obtained from BioMerieux (Lyon, France). These cells are grown in DMEM ("Dulbecco's Modified Eagle's Medium", Invitrogen 61965) for HaCaT cells, and MEM ("Modified Eagle's Medium", Invitrogen 41090); 10% fetal calf serum (SVF, Invitrogen, 10270, Lot 40Q5150K) in a humid chamber at 37 ° C. under 5% CO ₂ . HaCaT and MRC-5 cells were inoculated at 10 ⁴ cells / well in 96-well plate (Sarstedt 831835). After After 48 hours of growth, the culture medium is removed and replaced by the various "test" solutions (volume = 100 μL). After 24, 48 and / or 168 hours of contact time, the viability or cytotoxicity tests are carried out.

Biological test procedure

a) Cell viability tests (MTT test)

To evaluate the effect on viability of HaCaT and MRC-5 cells, of the various compounds tested, the technique of MTT (3- [4,5-dimethylthiazol-2-yl] -2,5-diphenyltetrazolium bromide; Aldrich, 135038), described by Mossman [Mosmann T. Rapid colorimetric assay for cell growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods. 1983; 65_: 55-63] and modified by Grare et al [Grare M, Mourer M, Fontanay S, Regnouf-Vains JB, Finance C, Duval RE. In vitro activity of para-guanidinoethylcalix [4] arene against susceptible and antibiotic-resistant Gram-negative and Gram-positive bacteria. J Antimicrob Chemother. 2007; 60: 575-81], was used.

It is based on the reduction of yellow tetrazolium salts in purple formazan crystals, mainly by mitochondrial dehydrogenases. The amount of formazan formed is proportional to the number of living cells. After 24, 48 and / or 168 hours of contact time with the different concentrations of the test molecules, 10 μL of MTT (5 mg / mL) are added to each of the wells and the plates are placed at 37 ° C. After 4 hours of incubation, the insoluble crystals of formazan that have formed are dissolved by adding 100 μl SDS to each of the wells. The absorbance is measured at 540 nm with a reference wavelength at 690 nm, using an ELISA plate reader (Multiskan EX, Thermo Electron Corporation, France). The results are the average of the values obtained for 8 wells per concentration and per time unit. Each experiment was performed 3 times.

b) Cytotoxicity tests (neutral red test)

The cytotoxicity test is based on the incorporation of a vital dye, Neutral Red, into the lysosomes of viable cells, following exposure of the cells to the different concentrations of the test molecules. The amount of dye, after extraction from the lysosomes, is quantified using a spectrophotometer and compared to that obtained in the case of "control" cells, not exposed to the test molecules.

The test was performed as previously described [Borenfreund E, Puerner JA. Toxicity determined in vitro by morphological alterations and neutral red absorption. Toxicol Lett 1985; 24: 119-24, and Grare M, Mourer M, Fontanay S, Regnouf-Vains JB, Finance C, Duval RE. In vitro activity of para-guanidinoethylcalix [4] arene against susceptible and antibiotic-resistant Gram-negative and Gram-positive bacteria. J Antimicrob Chemother. 2007; 60: 575-81].

After 24, 48 and / or 168 hours of contact time with the different concentrations of the test molecules, the medium contained in each of the wells is removed and replaced with 200 μL medium without phenol red (Invitrogen, 51200) containing 50 μg. / mL Neutral Red for an additional 3 h incubation. The cells are then rinsed 3 times with a solution of PBS. After the last PBS wash, 200 μL of a 1% acetic acid / 50% ethanol solution is added to each of the wells to extract the dye from the viable cell lysosomes. Absorbance is measured at 540 nm, with a reference wavelength at 690 nm, using an ELISA plate reader (Multiskan EX, Thermo Electron Corporation, France). The results are the average of the values obtained for 8 wells per concentration and per time unit. Each experiment was performed 3 times.

Results

The viability and cytotoxicity results are given in Tables 4 and 5.

Table 4: IC 50 determined from the values obtained by the viability test (at MTT). HaCaT and MRC-5 cell lines were cultured as an adherent culture on 96-well microplates.

The compounds were added at concentrations of 1 to 256 mg / L for 24, 48 and 168 h.

IC50s are representative of three independent determinations.

(1,6-bis (4- (2-guanidinoethyl) phenoxy] hexane.

Table 5: CC50 determined from the values obtained by the cytotoxicity test (at RN). HaCaT and MRC-5 cell lines were cultured as an adherent culture on 96-well microplates.

The compounds were added at concentrations of 1 to 256 mg / L for 24, 48 and 168 h. CC50s are representative of three independent determinations.

(1,1,6-bis (4- (2-guanidinoethyl) phenoxy] hexane

Comparison of the viability and cytotoxicity test results shows that IC50 (50% inhibitory concentration) and CC50 (cytotoxic

50%) obtained are in general agreement. The comparison of IC50 and CC50 values shows that the values are of the same order of magnitude in the case of hexamidine and chlorhexidine, those obtained for compound 6 being a little weaker. Therefore the Compound 6 has a somewhat more pronounced impact on viability and cytotoxicity, in vitro, on HaCaT and / or MRC5 eukaryotic cells.

Example 10: Determination of the selectivity index

From the MIC and IC50 concentrations determined after 24 hours of exposure, the selectivity index (IS = IC50 / MIC) was calculated (Table 4). The IS values obtained for the two tests (MTT and RN) are similar.

Table 6: Selectivity index obtained for 5 reference strains, after 24 hours of exposure to the compound, on HaCaT cell lines. (1,1,6-bis (4- (2-guanidinoethyl) phenoxy) hexane.

The IS values are globally very close to each other, which shows the interest of compound 6 vis-à-vis "commercial" compounds widely advocated "in town and in hospital" for Gram bacteria infections. positive, and more particularly S. aureus infections.

Claims

1. Use of at least one compound of the following formula (I)

wherein: n represents an integer from 1 to 12, especially from 1 to 8, m and m 'independently of one another represent integers from 1 to 8, q and q' independently represent one on the other hand integers from 0 to 2, p and p 'independently of one another represent integers from 0 to 4, - A and A' represent, independently of one another, a CH group ₂ , an NH group or a NR "group, wherein R" is an alkyl group of 1 to 3 carbon atoms, linear or branched,

B and B 'represent, independently of one another, an oxygen atom or a CH ₂ group; - R and R' are, independently of each other, a halogen, such as chlorine, bromine, iodine or fluorine, or an alkyl group of 1 to 3 carbon atoms, linear or branched,

for the preparation of a medicament for the treatment of pathologies associated with bacterial, fungal, parasitic and viral infections.

2. Use according to claim 1, of a compound of formula (II) below

(H) wherein A, A ', B, B', R, R ', m, m', n, p, p 'are as defined in claim 1, or a physiologically acceptable acid salt derived from a compound of formula (II) such as hydrochloride, formate, trifluoroacetate or oxalate (HOOCCOOH).

3. Use according to one of claims 1 and 2, of a compound of formula (III) below:

wherein A, B, R, m, n, p, are as defined in claim 1,

4. Use according to any one of claims 1 to 3, of a compound chosen from the compounds of formula (IV) below:

and in particular of a compound of formula 6 below:

Use according to claim 2 wherein m is different from m 'and / or p is different from p' and / or

- R is different from R ', and / or,

- A is different from A ', and / or, B is different from B '.

6. Use according to one of claims 1 to 5, wherein the medicament is for the treatment of pathologies caused by bacteria.

7. Use according to any one of claims 1 to 6, wherein the medicament is intended for the treatment of pathologies due to multidrug-resistant bacteria (BMR) associated such as nosocomial and / or community infections.

8. Use according to one of claims 1 to 5, wherein the medicament is intended for the treatment of pathologies caused by viruses belonging to different families, such as: the families Picornaviridae, Hepadnaviridae, Flaviviridae, Poxviridae, Herpesviridae, Coronaviridae, Parvoviridae, Papovavirus, Picornaviridae, Orthomyxoviridae, Flaviviridae, Togaviridae, Rhabdoviridae, Reoviridae, Arenaviridae, and the Bunyaviridae family.

9. Use according to one of claims 1 to 5, wherein the medicament is for the treatment of pathologies caused by fungi, such as Candida spp., Aspergillus spp., Epidermophyton spp., Trichophyton spp., Microsporum spp. and Pneumocystis jiroveci.

10. Use according to one of claims 1 to 5, wherein the medicament is for the treatment of pathologies caused by parasites, such as parasitic diseases due to protozoa or worms, scabies, myases and pediculosis , said parasites being chosen in particular from zoonoses, platyhelminthes and nemathelminthes.

11. Compound of formula (VI) below:

in which: n represents an integer from 1 to 12, especially from 1 to 8, q and q 'independently of one another represent integers from 0 to 2, p and p' independently represent one on the other, whole numbers from 0 to 4, B and B 'represent, independently of one another, an oxygen atom or a CH ₂ group,

the compounds of the following formulas being excluded:

12. Compound according to claim 11, of formula (I) below

wherein: n represents an integer from 1 to 12, especially from 1 to 8, q and q 'independently of one another represent integers from 0 to 2, p and p' independently represent 0 to 4, B and B 'are independently of one another an oxygen atom or a CH ₂ group, - R and R' are independently one of the other a halogen, such as chlorine, bromine, iodine or fluorine, or an alkyl group of 1 to 3 carbon atoms, linear or branched, if A and A 'represent, independently of one another, a CH group ₂ , then m and m 'independently of one another represent integers from 1 to 8, - if A and A' are independently of each other an NH group or an NR "group, wherein R "is an alkyl group of 1 to 3 carbon atoms, linear or branched, then m and m 'independently of one another represent integers from 2 to 8,

the compounds of the following formulas being excluded:

13. Compound according to one of claims 11 or 12, of a compound of formula (II) below:

wherein A, A ', B, B', R, R ', m, m', n, p, p 'are as defined in claim 11, or a physiologically acceptable acid salt derived from a compound of formula (II) such as hydrochloride, formate, trifluoroacetate or oxalate (HOOCCOOH).

14. Compound according to any one of claims 11 to 13, of formula (III) below:

wherein A, B, R, m, n, p are as defined in claim 11,

15. Compound according to any one of claims 11 to 14 of formula (IV) below:

and in particular compound of formula 6 below:

The compound of claim 13, wherein: - m is different from m ', and / or, p is different from p', and / or R is different from R ', and / or A is different from A ', and / or, - B is different from B'.

17. A pharmaceutical composition comprising as active substance at least one compound according to any one of claims 11 to 16 in association with a pharmaceutically acceptable vehicle.

18. Pharmaceutical composition according to claim 17, comprising as active substance a compound according to claim 13, wherein the sum m + m '+ n is less than or equal to 10, or a compound according to claim 14, for which the sum 2m + n is less than or equal to 10, the said pharmaceutical composition being formulated in aqueous solution.

19. Pharmaceutical composition according to claim 17, comprising as active substance a compound according to claim 13, in particular for which the sum m + m '+ n is greater than 10, or a compound according to claim 14, for which the sum 2m + n is greater than 10, said pharmaceutical composition being formulated in hydroalcoholic solution.

20. Pharmaceutical composition according to one of claims 17 to 19, orally administrable and such that the active substance is at a concentration of about 0.1 to about 5 mg / kg of body weight.

21. Pharmaceutical composition according to one of claims 17 to 19, administrable topically and such that the active substance is at a concentration of about 0.1% to about 1% in the pharmaceutical composition.

22. A process for preparing a compound of formula (Ia) comprising:

in which: n represents an integer from 1 to 12, especially from 1 to 8, m and m 'independently of one another represent integers from 2 to 8, q and q' independently represent one on the other hand integers from 0 to 2, p and p 'independently of one another represent integers from 0 to 4, - A and A' represent, independently of one another, an NH group or a group

NR ", in which R" is an alkyl group of 1 to 3 carbon atoms, linear or branched,

B and B 'represent, independently of one another, an oxygen atom or a CH ₂ group; - R and R' represent, independently of each other, a halogen, such as the chlorine atoms, bromine, iodine or fluorine, or an alkyl group of 1 to 3 carbon atoms, linear or branched,

Y represents a protective group of amines, in particular Boc or Fmoc.

to get :

a compound of formula (XF) below:

in which: n represents an integer from 1 to 12, in particular from 1 to 8, m and m 'independently of one another represent integers from 2 to 8, q and q 'independently of one another represent integers from 0 to 2, p and p' independently of one another represent integers from 0 to 4,

A and A 'independently of one another represent an NH group or a group

NR ", in which R" is an alkyl group of 1 to 3 carbon atoms, linear or branched,

an acid salt derived from a compound of formula (XF) such as a hydrochloride, a formate, a trifluoroacetate or an oxalate (HOOCCOOH).

b) a reaction step of the compound of formula (XI ') formed in step a) with a compound of formula (XII) below: y ^ p

Y (XII)

in which GP represents a Leaving Group

and Y represents a protective group of amines, in particular Boc or Fmoc, to obtain a compound of formula (XIIF) below:

in which: n represents an integer from 1 to 12, especially from 1 to 8, m and m 'independently of one another represent integers from 2 to 8, q and q' independently represent one on the other integers from 0 to 2, p and p 'independently of one another represent integers from 0 to 4, A and A 'independently of one another represent an NH group or a group

NR ", in which R" is an alkyl group of 1 to 3 carbon atoms, linear or branched,

Y represents a protective group of amines, in particular Boc or Fmoc.

a compound of formula (Ia) below:

wherein n: n represents an integer from 1 to 12, especially from 1 to 8, m and m 'independently of one another represent integers from 2 to 8, q and q' independently represent one of the other integers from 0 to 2, p and p 'independently of one another represent integers from 0 to 4,

A and A 'independently of one another represent an NH group or a group

NR ", in which R" is an alkyl group of 1 to 3 carbon atoms, linear or branched,

23. Preparation process according to claim 22 of a compound of formula (IV) comprising the following steps of:

a) a cleavage step of the Y groups of a compound of the following formula (XX)

to get :

a compound of formula (XXI) below:

wherein n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12, or

YN ^ GP

(XII) NHY

in which GP represents a Leaving Group such as -SR, -NTf or

and Y represents a protective group of the amines, in particular Boc or Fmoc, to obtain a compound of formula (XXII) below:

a compound of formula (IV) below:

wherein n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12, or

an acid salt derived from a compound of formula (IV) such as a hydrochloride, a formate, a trifluoroacetate or an oxalate (HOOCCOOH),

24. Compound of formula (X ') below:

in which: n represents an integer from 1 to 12, in particular from 1 to 8, m and m 'independently of one another represent integers from 2 to 8, q and q' independently represent number of integers from 0 to 2, p and p 'independently of one another represent integers from 0 to 4, - A and A' represent, independently of one another, a group NH or a group

NR ", in which R" is an alkyl group of 1 to 3 carbon atoms, linear or branched, - B and B 'represent, independently of one another, an oxygen atom or a CH ₂ group,

R and R 'represent, independently of one another, a halogen, such as chlorine, bromine, iodine or fluorine atoms, or an alkyl group of 1 to 3 carbon atoms, linear or branched, Y represents a protective group of amines, in particular Boc or Fmoc.

in particular a compound of formula (XX) below:

25. Compound according to claim 24, as an intermediate for the preparation of the compounds of formula (I) defined in claim 1, and in particular compound of formula (XX) as an intermediate for the preparation of the compounds of formula (IV) defined in claim 4.

26. A process for preparing a compound of formula (Ic) comprising the following steps of:

a) a reaction step between a compound of formula (XXX) below:

IU (XXX) in which:

X and X 'represent, independently of one another, a halogen, especially a chlorine, a bromine or an iodine, n represents an integer from 1 to 12, in particular from 1 to 8,

with a compound of formula (XXXI) below:

in which: m represents an integer from 1 to 8, q represents an integer from 0 to 2, p represents an integer from 0 to 4, R represents a halogen, such as chlorine, bromine, iodine or fluorine atoms, or an alkyl group of 1 to 3 carbon atoms, linear or branched,

b) followed by a reaction step with a compound of formula (XXXII) below:

(XXXII)

in which: m 'represents an integer from 1 to 8,

q 'represents an integer from 0 to 2, p' represents an integer from 0 to 4,

R 'represents a halogen, such as the chlorine, bromine, iodine or fluorine atoms, or an alkyl group of 1 to 3 carbon atoms, linear or branched,

steps a) and b) can be performed simultaneously or successively,

to obtain the compound of formula (XXXIII) below

(XXXIII)

c) followed by a Pinner reaction step,

to form a compound of formula (Ic) below

or a physiologically acceptable acid salt derived from a compound of formula (Ic) such as a hydrochloride, a formate, a trifluoroacetate or an oxalate (HOOCCOOH).

27. A process for preparing a compound of formula (Id) comprising the following steps of

a) an alkylation step of a compound of formula (XXXIV) below:

(XXXIV)

to obtain a compound of formula (XXXV) below

b) followed by one or more homologation steps to obtain the compound of formula (XXXVI) below:

(XXXVI)

c) followed by a Pinner reaction step, to form a compound of the following formula (Id)

wherein: n represents an integer from 1 to 12, especially from 1 to 8, - m and m 'independently of one another represent integers from 1 to 8, q and q' independently represent one of the other of integers from 0 to 2, p and p 'independently of one another represent integers from 0 to 4, R and R' are independently of each other a halogen, such as chlorine, bromine, iodine or fluorine atoms, or an alkyl group of 1 to 3 carbon atoms, linear or branched,